Paget was born at Great Yarmouth, England, on January 11, 1814, the son of a brewer and shipowner. He was one of a large family, and his brother Sir George Paget (1809 - 1892), who became Regius Professor of Physic at the University of Cambridge in 1872, also had a distinguished career in medicine and was made a K.C.B.. He attended a day-school in Yarmouth, and afterwards was destined for the navy; but this plan was given up, and at the age of sixteen he was apprenticed to a general practitioner, whom he served for four and a half years, during which time he gave his leisure hours to botanising, and made a great collection of the flora of East Norfolk. At the end of his apprenticeship he published with one of his brothers a very careful Sketch of the Natural History of Yarmouth and its Neighbourhood.

In October 1834 he entered as a student at St Bartholomew's Hospital, in London. Here he is noted to have described the first journal club. Medical students in those days were left very much to themselves; there was no close supervision of their work, but it is probable that Paget gained rather than lost by having to fight his own way. He swept the board of prizes in 1835, and again in 1836; and in his first winter session he discovered the pathogen for trichinosis, a parasitic disease caused by Trichina spiralis, a minute roundworm that infests the muscles of the human body, and which is usually acquired by eating infected pork. In May 1836 he passed his examination at the Royal College of Surgeons, and became qualified to practice. The next seven years (1836 - 1843) were spent in London lodgings, and were a time of poverty, for he made only 15 pounds a year by practice, and his father, having failed in business, could not give him any help. He managed to keep himself by writing for the medical journals, and preparing the catalogues of the hospital museum and of the pathological museum of the Royal College of Surgeons. In 1836 he had been made curator of the hospital museum, and in 1838 demonstrator of morbid anatomy at the hospital; but his advancement there was hindered by the privileges of the hospital apprentices, and by the fact that he had been too poor to afford a house-surgeoncy, or even a dressership.

In 1841 he was made surgeon to the Finsbury Dispensary; but this appointment did not give him any experience in the graver operations of surgery. In 1843 he was appointed lecturer on general anatomy (microscopic anatomy) and physiology at the hospital, and warden of the hospital college then founded. For the next eight years he lived within the walls of the hospital, in charge of about thirty students resident in the little college. Besides his lectures and his superintendence of the resident students, he had to enter all new students, to advise them how to work, and to manage the finances and the general affairs of the school. Thus he was constantly occupied with the business of the school, and often passed a week, or more, without going outside the hospital gates.

In 1844 he married Lydia, youngest daughter of the Rev. Henry North. In 1847 he was appointed an assistant-surgeon to the hospital, and Arris and Gale professor at the Royal College of Surgeons. He held this professorship for six years and each year gave six lectures in surgical pathology. The first edition of these lectures, which were the chief scientific work of his life, was published in 1853 as Lectures on Surgical Pathology. In 1851 he was elected a Fellow of the Royal Society. In October 1851 he resigned the wardenship of the hospital. He had now become known as a great physiologist and pathologist: he had done for pathology in England what Rudolf Virchow had done in Germany; but he had hardly begun to get into practice, and he had kept himself poor that he might pay his share of his fathers debts - a task that took him fourteen years to fulfill.

Paget was the father of the Right Reverend Francis Paget, Bishop of Oxford, and of Stephen Paget, an English surgeon who first proposed the "seed and soil" theory of metastasis. Paget was friends with Charles Darwin and Thomas Henry Huxley. He was a committed Christian and maintained that there was no conflict between religion and science.

It is probable that no famous surgeon, not even John Hunter (1728 - 1793), ever founded his practice deeper in science than Paget did, or waited longer for his work to come back to him. In physiology he had mastered the chief English, French, German, Dutch and Italian literature of the subject, and by incessant study and microscope work had put himself level with the most advanced knowledge of his time; so that it was said of him by Robert Owen, in 1851, that he had his choice, either to be the first physiologist in Europe, or to have the first surgical practice in London, with a baronetcy. His physiological lectures at St Bartholomew's Hospital were the chief cause of the rise in the fortunes of its school, which in 1843 had gone down to a low point.

In pathology his work was even more important. He fills the place in pathology that had been left empty by Hunter's death in 1793; the time of transition from Hunter's teaching, which for all its greatness was hindered by want of the modern microscope, to the pathology and bacteriology of the present day. It is Paget's greatest achievement that he made pathology dependent, in everything, on the use of the microscope, especially the pathology of tumors. He and Virchow may truly be called the founders of modern pathology; they stand together, Paget's Lectures on Surgical Pathology and Virchow's Cellulär-Pathologie.

When Paget, in 1851, began practice near Cavendish Square, he had still to wait a few years more for success in professional life. The turn of the tide came about 1854 or 1855; and in 1858 he was appointed surgeon extraordinary to Queen Victoria, and in 1863 surgeon in ordinary to the Prince of Wales. He had for many years the largest and most arduous surgical practice in London. His days work was seldom less than sixteen or seventeen hours. Cases sent to him for final judgment, with especial frequency, were those of tumours, and of all kinds of disease of the bones and joints, and all neurotic cases having symptoms of surgical disease. His supremacy lay rather in the science than in the art of surgery, but his name is also associated with certain great practical advances. He discovered the Paget's disease of the breast and the Paget's disease of the bones (osteitis deformans) which are named after him; and he was the first to urge removal of the tumour, instead of amputation of the limb, in cases of myeloid sarcoma. In 1870, he was elected a foreign member of the Royal Swedish Academy of Sciences.

In 1871 he nearly died from infection at a post mortem examination, and, to lighten the weight of his work, was obliged to resign his surgeoncy to the hospital. In this same year he received the honour of the baronetcy of Harewood Place (Middlesex). In 1874 he received an honorary degree from the University of Cambridge. In 1875 he was president of the Royal College of Surgeons, and in 1877 Hunterian orator. In 1878 he gave up operating, but for eight or ten years longer he still had a very heavy consulting practice. In 1881 he was president of the International Medical Congress held in London; in 1880 he gave, at Cambridge, a memorable address on Elemental Pathology, setting forth the likeness of certain diseases of plants and trees to those of the human body.

Besides shorter writings he also published Clinical Lectures and Essays (1st ed. 1875) and Studies of Old Case-books (1891). In 1883, on the death of Sir George Jessel, he was appointed vice-chancellor of the University of London. In 1889 he was appointed a member of the Royal Commission on Vaccination.

In May 1886 he treated Edward Crowley, father of Aleister Crowley for tongue cancer. An operation was advised but Crowley declined and died the following year.

He died in London on December 30, 1899, at the age of 85.

Sir James Paget had the gift of eloquence, and was one of the most careful and most delightful speakers of his time. He had a natural and unaffected pleasure in society, and he loved music. He possessed the rare gift of ability to turn swiftly from work to play; enjoying his holidays like a schoolboy, easily moved to laughter, keen to get the maximum of happiness out of very ordinary amusements, emotional in spite of incessant self-restraint, vigorous in spite of constant overwork. In him a certain light-hearted enjoyment was combined with the utmost reserve, unfailing religious faith, and the most scrupulous honour. He was all his life profoundly indifferent toward politics, both national and medical; his ideal was the unity of science and practice in the professional life.

Sir James's reputation remains high due to his work as a surgeon and medical research and work. But he also had an apparent interest in criminal matters. In 1886 he followed the poisoning trial of Adelaide Bartlett for the murder of her husband Edwin. After a spirited defense by Sir Edward Clarke Bartlett was acquitted. The key problem of the trial was that Edwin was poisoned by liquid chloroform, which was found in his stomach. But liquid chloroform burns the throat if swallowed, and the drinker would be screaming. Edwin Bartlett never screamed the night he died. As a result an alternative theory of suicide was considered and helped get the acquittal. But it left the public unsatisfied. Paget, upon hearing the result, made the comment he is best remembered for: "Now that she has been acquitted for murder and cannot be tried again, she should tell us in the interest of science how she did it!" Paget's interests in crime were shared by his son John Paget, who wrote a book Puzzles and Paradoxes about several famous historical mysteries.