Modigliani was born into a Jewish family in Livorno, Italy. A port city, Livorno had long served as a refuge for those persecuted for their religion, and was home to a large Jewish community. His maternal great-great-grandfather, Solomon Garsin, had immigrated to Livorno in the 18th century as a refugee. Modigliani was the fourth child of Flaminio Modigliani and his French wife, Eugenia Garsin. His father was a money-changer, but when his business failed, the family lived in poverty. Amedeo's birth saved the family from ruin, as according to an ancient law, creditors could not seize the bed of a pregnant woman or a mother with a newborn child. The bailiffs entered the family's home just as Eugenia went into labour; the family protected their most valuable assets by piling them on top of her. Modigliani had a close relationship with his mother, who taught him at home until he was ten. Beset with health problems after an attack of pleurisy when he was about eleven, a few years later he developed a case of typhoid fever. When he was sixteen he was taken ill again and contracted the tuberculosis which would later claim his life. After Modigliani recovered from the second bout of pleurisy, his mother took him on a tour of southern Italy: Naples, Capri, Rome and Amalfi, then north to Florence and Venice. His mother was, in many ways, instrumental in his ability to pursue art as a vocation. Modigliani is known to have drawn and painted from a very early age, and thought himself "already a painter", his mother wrote, even before beginning formal studies. Despite her misgivings that launching him on a course of studying art would impinge upon his other studies, his mother indulged the young Modigliani's passion for the subject. At the age of fourteen, while sick with typhoid fever, he raved in his delirium that he wanted, above all else, to see the paintings in the Palazzo Pitti and the Uffizi in Florence. As Livorno's local museum only housed a sparse few paintings by the Italian Renaissance masters, the tales he had heard about the great works held in Florence intrigued him, and it was a source of considerable despair to him, in his sickened state, that he might never get the chance to view them in person. His mother promised that she would take him to Florence herself, the moment he was recovered. Not only did she fulfil this promise, but she also undertook to enroll him with the best painting master in Livorno, Guglielmo Micheli.

Modigliani worked in Micheli's Art School from 1898 to 1900. Here his earliest formal artistic instruction took place in an atmosphere deeply steeped in a study of the styles and themes of 19th-century Italian art. In his earliest Parisian work, traces of this influence, and that of his studies of Renaissance art, can still be seen: this nascent work was shaped as much by such artists as Giovanni Boldini as by Toulouse-Lautrec. Modigliani showed great promise while with Micheli, and only ceased his studies when he was forced to, by the onset of tuberculosis.

In 1901, whilst in Rome, Modigliani admired the work of Domenico Morelli, a painter of melodramatic Biblical studies and scenes from great literature. It is ironic that he should be so struck by Morelli, as this painter had served as an inspiration for a group of iconoclasts who went known by the title "the Macchiaioli" (from macchia — "dash of colour", or, more derogatively, "stain"), and Modigliani had already been exposed to the influences of the Macchiaioli. This minor, localized landscape movement was possessed of a need to react against the bourgeois stylings of the academic genre painters. While sympathetically connected to (and actually pre-dating) the French Impressionists, the Macchiaioli did not make the same impact upon international art culture as did the contemporaries and followers of Monet, and are today largely forgotten outside of Italy. Modigliani's connection with the movement was through Guglielmo Micheli, his first art teacher. Micheli was not only a Macchiaiolo himself, but had been a pupil of the famous Giovanni Fattori, a founder of the movement. Micheli's work, however, was so fashionable and the genre so commonplace that the young Modigliani reacted against it, preferring to ignore the obsession with landscape that, as with French Impressionism, characterized the movement. Micheli also tried to encourage his pupils to paint en plein air, but Modigliani never really got a taste for this style of working, sketching in cafés, but preferring to paint indoors, and especially in his own studio. Even when compelled to paint landscapes (three are known to exist), Modigliani chose a proto-Cubist palette more akin to Cézanne than to the Macchiaioli.

While with Micheli, Modigliani not only studied landscape, but also portraiture, still-life, and the nude. His fellow students recall that the latter was where he displayed his greatest talent, and apparently this was not an entirely academic pursuit for the teenager: when not painting nudes, he was occupied with seducing the household maid. Despite his rejection of the Macchiaioli approach, Modigliani nonetheless found favour with his teacher, who referred to him as "Superman", a pet name reflecting the fact that Modigliani was not only quite adept at his art, but also that he regularly quoted from Nietzsche's Thus Spoke Zarathustra. Fattori himself would often visit the studio, and approved of the young artist's innovations.

In 1902, Modigliani continued what was to be a life-long infatuation with life drawing, enrolling in the Accademia di Belle Arti (Scuola Libera di Nudo, or "Free School of Nude Studies") in Florence. A year later while still suffering from tuberculosis, he moved to Venice, where he registered to study at the Istituto di Belle Arti. It is in Venice that he first smoked hashish and, rather than studying, began to spend time frequenting disreputable parts of the city. The impact of these lifestyle choices upon his developing artistic style is open to conjecture, although these choices do seem to be more than simple teenage rebellion, or the cliched hedonism and bohemianism that was almost expected of artists of the time; his pursuit of the seedier side of life appears to have roots in his appreciation of radical philosophies, including those of Nietzsche. Having been exposed to erudite philosophical literature as a young boy under the tutelage of Isaco Garsin, his maternal grandfather, he continued to read and be influenced through his art studies by the writings of Nietzsche, Baudelaire, Carducci, Comte de Lautréamont, and others, and developed the belief that the only route to true creativity was through defiance and disorder. Letters that he wrote from his 'sabbatical' in Capri in 1901 clearly indicate that he is being more and more influenced by the thinking of Nietzsche. The work of Lautréamont was equally influential at this time. This doomed poet's Les Chants de Maldoror became the seminal work for the Parisian Surrealists of Modigliani's generation, and the book became Modigliani's favourite to the extent that he learnt it by heart. The poetry of Lautréamont is characterized by the juxtaposition of fantastical elements, and by sadistic imagery; the fact that Modigliani was so taken by this text in his early teens gives a good indication of his developing tastes. Baudelaire and D'Annunzio similarly appealed to the young artist, with their interest in corrupted beauty, and the expression of that insight through Symbolist imagery.

Modigliani wrote to Ghiglia extensively from Capri, where his mother had taken him to assist in his recovery from tuberculosis. These letters are a sounding board for the developing ideas brewing in Modigliani's mind. Ghiglia was seven years Modigliani's senior, and it is likely that it was he who showed the young man the limits of his horizons in Livorno. Like all precocious teenagers, Modigliani preferred the company of older companions, and Ghiglia's role in his adolescence was to be a sympathetic ear as he worked himself out, principally in the convoluted letters that he regularly sent, and which survive today.

In 1906 Modigliani moved to Paris, then the focal point of the avant-garde. In fact, his arrival at the centre of artistic experimentation coincided with the arrival of two other foreigners who were also to leave their marks upon the art world: Gino Severini and Juan Gris. He settled in Le Bateau-Lavoir, a commune for penniless artists in Montmartre, renting himself a studio in Rue Caulaincourt. Even though this artists' quarter of Montmartre was characterized by generalized poverty, Modigliani himself presented — initially, at least — as one would expect the son of a family trying to maintain the appearances of its lost financial standing to present: his wardrobe was dapper without ostentation, and the studio he rented was appointed in a style appropriate to someone with a finely attuned taste in plush drapery and Renaissance reproductions. He soon made efforts to assume the guise of the bohemian artist, but, even in his brown corduroys, scarlet scarf and large black hat, he continued to appear as if he were slumming it, having fallen upon harder times. When he first arrived in Paris, he wrote home regularly to his mother, he sketched his nudes at the Académie Colarossi, and he drank wine in moderation. He was at that time considered by those who knew him as a bit reserved, verging on the asocial. He is noted to have commented, upon meeting Picasso who, at the time, was wearing his trademark workmen's clothes, that even though the man was a genius, that did not excuse his uncouth appearance.

Within a year of arriving in Paris, however, his demeanour and reputation had changed dramatically. He transformed himself from a dapper academician artist into a sort of prince of vagabonds. The poet and journalist Louis Latourette, upon visiting the artist's previously well-appointed studio after his transformation, discovered the place in upheaval, the Renaissance reproductions discarded from the walls, the plush drapes in disarray. Modigliani was already an alcoholic and a drug addict by this time, and his studio reflected this. Modigliani's behaviour at this time sheds some light upon his developing style as an artist, in that the studio had become almost a sacrificial effigy for all that he resented about the academic art that had marked his life and his training up to that point. Not only did he remove all the trappings of his bourgeois heritage from his studio, but he also set about destroying practically all of his own early work. The motivation for this violent rejection of his earlier self is the subject of considerable speculation. The self-destructive tendencies may have stemmed from his tuberculosis and the knowledge (or presumption) that the disease had essentially marked him for an early death; within the artists' quarter, many faced the same sentence, and the typical response was to set about enjoying life while it lasted, principally by indulging in self-destructive actions. For Modigliani such behaviour may have been a response to a lack of recognition; he sought the company of artists such as Utrillo and Soutine, seeking acceptance and validation for his work from his colleagues. Modigliani's behavior stood out even in these Bohemian surroundings: he carried on frequent affairs, drank heavily, and used absinthe and hashish. While drunk, he would sometimes strip himself naked at social gatherings. He became the epitome of the tragic artist, creating a posthumous legend almost as well-known as that of Vincent van Gogh.

During the 1920s, in the wake of Modigliani's career and spurred on by comments by André Salmon crediting hashish and absinthe with the genesis of Modigliani's style, many hopefuls tried to emulate his "success" by embarking on a path of substance abuse and bohemian excess. While this propaganda served as a rallying cry to those with a romantic longing to be a tragic, doomed artist, these strategies did not produce unique artistic insights or techniques in those who did not already have them. In fact, art historians suggest that it is entirely possible for Modigliani to have achieved even greater artistic heights had he not been immured in, and destroyed by, his own self-indulgences.

During his early years in Paris, Modigliani worked at a furious pace. He was constantly sketching, making as many as a hundred drawings a day. However, many of his works were lost — destroyed by him as inferior, left behind in his frequent changes of address, or given to girlfriends who did not keep them. He was first influenced by Henri de Toulouse-Lautrec, but around 1907 he became fascinated with the work of Paul Cézanne. Eventually he developed his own unique style, one that cannot be adequately categorized with other artists. He met the first serious love of his life, Russian poet Anna Akhmatova, in 1910, when he was 26. They had studios in the same building, and although 21-year-old Anna was recently married, they began an affair. Tall (Modigliani was only 5 foot 5 inches) with dark hair (like Modigliani's), pale skin and grey-green eyes, she embodied Modigliani's aesthetic ideal and the pair became engrossed in each other. After a year, however, Anna returned to her husband.

In 1909, Modigliani returned home to Livorno, sickly and tired from his wild lifestyle. Soon he was back in Paris, this time renting a studio in Montparnasse. He originally saw himself as a sculptor rather than a painter, and was encouraged to continue after Paul Guillaume, an ambitious young art dealer, took an interest in his work and introduced him to sculptor Constantin Brancusi. Although a series of Modigliani's sculptures were exhibited in the Salon d'Automne of 1912, by 1914 he abandoned sculpting and focused solely on his painting, a move precipitated by the difficulty in acquiring sculptural materials due to the outbreak of war, and by Modigliani's physical debilitation.

In Modigliani's art, there is evidence of the influence of art from Africa and Cambodia which he may have seen in the Musée de l'Homme, but his stylizations are just as likely to have been the result of his being surrounded by Mediæval sculpture during his studies in Northern Italy (there is no recorded information from Modigliani himself, as there is with Picasso and others, to confirm the contention that he was influenced by either ethnic or any other kind of sculpture). A possible interest in African tribal masks seems to be evident in his portraits. In both his painting and sculpture, the sitters' faces resemble ancient Egyptian painting in their flat and mask-like appearance, with distinctive almond eyes, pursed mouths, twisted noses, and elongated necks. However these same characteristics are shared by Mediæval European sculpture and painting.

Modigliani painted a series of portraits of contemporary artists and friends in Montparnasse: Chaim Soutine, Moise Kisling, Pablo Picasso, Diego Rivera, Marie "Marevna" Vorobyev-Stebeslka, Juan Gris, Max Jacob, Blaise Cendrars, and Jean Cocteau, all sat for stylized renditions.

At the outset of World War I, Modigliani tried to enlist in the army but was refused because of his poor health.

Known as Modì, which translates as 'cursed' (maudit), by many Parisians, but as Dedo to his family and friends, Modigliani was a handsome man, and attracted much female attention. Women came and went until Beatrice Hastings entered his life. She stayed with him for almost two years, was the subject for several of his portraits, including Madame Pompadour, and the object of much of his drunken wrath. When the British painter Nina Hamnett arrived in Montparnasse in 1914, on her first evening there the smiling man at the next table in the café introduced himself as Modigliani; painter and Jew. They became great friends. In 1916, Modigliani befriended the Polish poet and art dealer Leopold Zborovski and his wife Anna. The following summer, the Russian sculptor Chana Orloff introduced him to a beautiful 19-year-old art student named Jeanne Hébuterne, who had posed for Tsuguharu Foujita. From a conservative bourgeois background, Hébuterne was renounced by her devout Roman Catholic family for her liaison with the painter, whom they saw as little more than a debauched derelict, and, worse yet, a Jew. Despite her family's objections, soon they were living together, and although Hébuterne was the current love of his life, their public scenes became more renowned than Modigliani's individual drunken exhibitions.

On December 3, 1917, Modigliani's first one-man exhibition opened at the Berthe Weill Gallery. The chief of the Paris police was scandalized by Modigliani's nudes and forced him to close the exhibition within a few hours after its opening.

After he and Hébuterne moved to Nice, she became pregnant and on November 29, 1918 gave birth to a daughter whom they named Jeanne (1918-1984).

On a trip to Nice which had been conceived and organized by Leopold Zborovski, Modigliani, Foujita and other artists tried to sell their works to rich tourists. Modigliani managed to sell a few pictures but only for a few francs each. Despite this, during this time he produced most of the paintings that later became his most popular and valued works. During his lifetime he sold a number of his works, but never for any great amount of money. What funds he did receive soon vanished for his habits.

In May 1919 he returned to Paris, where, with Hébuterne and their daughter, he rented an apartment in the rue de la Grande Chaumière. While there, both Jeanne Hébuterne and Amedeo Modigliani painted portraits of each other, and of themselves. Although he continued to paint, Modigliani's health was deteriorating rapidly, and his alcohol-induced blackouts became more frequent. In 1920, after not hearing from him for several days, his downstairs neighbor checked on the family and found Modigliani in bed delirious and holding onto Hébuterne who was nearly nine months pregnant. They summoned a doctor, but little could be done because Modigliani was dying of the then-incurable disease tubercular meningitis. Modigliani died on January 24, 1920. There was an enormous funeral, attended by many from the artistic communities in Montmartre and Montparnasse. Hébuterne was taken to her parents' home, where, inconsolable, she threw herself out of a fifth-floor window two days after Modigliani's death, killing herself and her unborn child. Modigliani was interred in Père Lachaise Cemetery. Hébuterne was buried at the Cimetière de Bagneux near Paris, and it was not until 1930 that her embittered family allowed her body to be moved to rest beside Modigliani. A single tombstone honors them both. His epitaph reads: "Struck down by Death at the moment of glory." Hers reads: "Devoted companion to the extreme sacrifice."

Modigliani died penniless and destitute—managing only one solo exhibition in his life and giving his work away in exchange for meals in restaurants. Since his death his reputation has soared. Nine novels, a play, a documentary and three feature films have been devoted to his life.