After initial study with his father, Paganini studied with a local violinist, G. Servetto, and then with the celebrated Giacomo Costa. He made his first appearance in 1793 and then studied with Alessandro Rolla and Gaspare Ghiretti at Parma. In 1797, accompanied by his father, he toured Lombardy, where with each concert his reputation grew. Gaining his independence soon after, he indulged excessively in gambling and romantic love affairs. At one point he pawned his violin because of gambling debts; a French merchant lent him a Guarneri violin to play a concert and, after hearing him, gave him the instrument.

Between 1801 and 1807 he wrote the 24 Capricci for unaccompanied violin, displaying the novel features of his technique, and the two sets of six sonatas for violin and guitar. He reappeared in Italy as a violinist in 1805 and was appointed director of music at Piombino by Napoleon's sister, Élisa Bonaparte Baciocchi. He later gave recitals of his own compositions in many towns in Italy and in 1815 formed his long attachment with the dancer Antonia Bianchi.

In 1828 Paganini experienced great success in Vienna, and his appearances in Paris and London in 1831 were equally sensational. His tour of England and Scotland in 1832 made him a wealthy man. In 1833 he settled in Paris, where he commissioned Hector Berlioz to write his symphony Harold en Italie. Paganini thought that the challenge of its viola solo was too slight, however, and he never played it. Following the failure of the Casino Paganini, a gambling house in which he had invested, he went to Marseille in 1839, then to Nice.

Paganini's romantic personality and adventures created in his own day the legend of a Mephistophelean figure. Stories circulated that he was in league with the devil and that he had been imprisoned for murder; his burial in consecrated ground was delayed for five years. He was long regarded as a miser, but a more accurate portrait would consider his desire to be free from a train of dependent followers and their importunities for his largesse. His gift of 20,000 francs to the struggling composer Berlioz (Berlioz, Hector) was an act of generosity seemingly uncharacteristic; possibly Paganini, recognizing in “Beethoven's successor” a worthy talent, thought it was his duty to come to the composer's aid.

His violin technique, based on that of his works, principally the Capricci, the violin concertos, and the sets of variations, demanded a wide use of harmonics and pizzicato effects, new methods of fingering and even of tuning. In performance he improvised brilliantly. He was also a flamboyant showman who used trick effects such as severing one or two violin strings and continuing the piece on the remaining strings. His technical innovations were imitated by later virtuosi, notably Pablo Sarasate and Eugène Ysaÿe. His other works include 6 violin concertos, of which the first, in D major, is especially popular; 12 sonatas for violin and guitar; and 6 quartets for violin, viola, cello, and guitar. The influence of his virtuosity extended to orchestral as well as to piano music. His influence on Franz Liszt (Liszt, Franz) was immense. Themes from the Capricci inspired works by Liszt, Robert Schumann, Johannes Brahms, and Sergey Rachmaninoff.