The French invaded northern Italy in March 1796, and Genoa was not spared. The Paganinis sought refuge in their country property in Ramairone. By 1800, Paganini and his father traveled to Livorno, where Paganini played in concerts and his father resumed his maritime work. In 1801, Paganini, aged 18 at the time, was appointed first violin of the Republic of Lucca, but a substantial portion of his income came from freelancing. His fame as a violinist was matched only by his reputation as a gambler and womanizer. In 1805, Lucca was annexed by Napoleonic France, and the region was ceded to Napoleon's sister, Elisa Baciocchi. Paganini became a violinist for the Baciocchi court, while giving private lessons for her husband, Felice. In 1807, Baciocchi became the Grand Duchess of Tuscany and her court was transferred to Florence. Paganini was part of the entourage, but, towards the end of 1809, he left Baciocchi to resume his freelance career.

For the next few years, Paganini returned to touring in the areas surrounding Parma and Genoa. Though he was very popular with the local audience, he was still not very well known in Europe. His first break came from an 1813 concert which took place at La Scala in Milan. The concert was a great success, and as a result Paganini began to attract the attention of other prominent, albeit more conservative, musicians across Europe. His early encounters with Charles Philippe Lafont and Ludwig Spohr created intense rivalry. His concert activities, however, were still limited to Italy for the next few years.

His fame spread across Europe with a concert tour that started in Vienna in August, 1828, stopping in every major European city in Germany, Poland, and Bohemia until February, 1831 in Strasburg. This was followed by tours in Paris and the United Kingdom of Great Britain and Ireland. His technical ability and his willingness to display it received much critical acclaim. In addition to his own compositions, theme and variations being the most popular, Paganini also performed modified versions of works (primarily concertos) written by his early contemporaries, such as Rodolphe Kreutzer and Giovanni Battista Viotti.

Throughout his life, Paganini was no stranger to chronic illnesses, as he suffered from Marfan syndrome. His frequent concert schedule, as well as his extravagant lifestyle, eventually took their toll on his health. He was diagnosed with syphilis as early as 1822, and his remedy, which included mercury and opium, resulted in serious health and psychological problems. In 1834, while still in Paris, he was treated for pulmonary tuberculosis. Though his recovery was reasonably quick, his future career was marred with frequent cancellations due to various health problems, from the common cold to depression, which lasted from days to months.

In 1836, Paganini returned to Paris to set up a casino. Its immediate failure left him in financial ruins, and he auctioned off his personal effects, including his musical instruments, to recoup his losses. On Christmas of 1838, he left Paris for Marseilles and, after a brief stay, traveled to Nice where he fell ill once more. Paganini, wrongly assuming it to be a premature gesture, refused the Last Rites to be performed on him by a priest from the local parish. However, on 27 May 1840, Paganini died from internal hemorrhaging before a priest could be summoned.

It was on these grounds, and his widely rumored association with the devil, that his body was denied a Catholic burial in Genoa. It took four years, and an appeal to the Pope, before the body was allowed to be transported to Genoa, but was still not buried. His remains were finally put to rest in 1876 in a cemetery in Parma. In 1893, the Czech violinist, František Ondříček, persuaded Paganini's grandson, Attila, to allow a viewing of the violinist's body. After the bizarre episode, Paganini's body was finally reinterred in a new cemetery in Parma in 1896.

Though having no shortage of romantic conquests, Paganini was once seriously involved with a singer named Antonia Bianchi from Como, whom he met in Milan in 1813. The two concertized together throughout Italy. They had a son, Achilles Cyrus Alexander, born on 23 July 1825, in Palermo and baptized at San Bartolomeo's. Their union was never legalized and it ended around April 1828 in Vienna. Paganini brought Achilles on his European tours, and Achilles would later accompany his father until the latter's death. He was instrumental in dealing with his father's burial, years after his death.

Throughout his career, Paganini also became close friends with composers Gioachino Rossini and Hector Berlioz. Rossini and Paganini met in Bologna in the summer of 1818. In January 1821, on his return from Naples, Paganini met Rossini again in Rome, just in time to become the composer's substitute conductor for his opera Mathilde de Sharbran, upon the sudden death of the original conductor. The violinist's efforts earned gratitude from the composer. Meanwhile, Paganini was introduced to Berlioz in Paris in 1833. Though Paganini also commissioned from him Harold en Italie for viola and orchestra, he never performed it, and instead it was premiered a year later by violist Christian Urhan. Despite his alleged lack of interest in Harold, Paganini often referred to Berlioz as the resurrection of Beethoven and, towards the end of his life, he gave large sums to the composer.

Paganini was in possession of a number of fine string instruments. More legendary than these were the circumstances under which he obtained (and lost) some of them. While Paganini was still a teenager in Livorno, a wealthy businessman named Livron lent him a violin, made by the master luthier Guarneri, for a concert. Livron was so impressed with Paganini's playing that he refused to take it back. This particular violin would come to be known as Il Cannone Guarnerius. On a later occasion in Parma, he won another valuable violin (also by Guarneri) after a difficult sight-reading challenge brought on by a man named Pasini. Other instruments associated with Paganini include the Antonio Amati 1600, the Nicolò Amati 1657, the Paganini-Desaint 1680 Stradivari, the Guarneri-filius Andrea 1706, the Le Brun 1712 Stradivari, the Vuillaume c.1720 Bergonzi, the Hubay 1726 Stradivari, and the Comte Cozio di Salabue 1727 violins; the Countess of Flanders 1582 da Salò-di Bertolotti, and the Mendelssohn 1731 Stradivari violas; the Piatti 1700 Goffriller, the Stanlein 1707 Stradivari, and the Ladenburg 1736 Stradivari cellos; and the Grobert of Mirecourt 1820 (guitar).