Born into a peasant family, Pichegru taught mathematics at the military academy at Brienne before he joined an artillery regiment in 1780. He was sergeant major at the outbreak of the Revolution in 1789 and in 1792 became lieutenant colonel. Appointed commander of the Army of the Rhine in October 1793, he helped General Lazare Hoche (Hoche, Lazare) drive the Austro-Prussian armies from Alsace in December. Nevertheless, Pichegru was jealous of Hoche. By convincing the government that Hoche was a traitor, he managed to have his rival imprisoned (March 1794). Pichegru was given command of the 150,000 troops of the Army of the North.

In April 1794, Pichegru and General Jean-Baptiste Jourdan (Jourdan, Jean-Baptiste, Count), commander of the Army of the Moselle, launched an invasion of the Austrian Netherlands, capturing Amsterdam by January 1795. Returning to Paris, Pichegru was hailed as a saviour of his country. Although he was appointed commander of the Armies of the Rhine and Moselle in mid-1795, he had already begun to turn against France's republican regime. He initiated secret contacts with agents of French émigrés in August.

In March 1796, Pichegru resigned his commission. Elected president of the Council of Five Hundred (the lower chamber of the legislature) in May 1797, he sided with the royalist deputies. Nevertheless, word of his previous treasonable contacts reached Paris, and, when the royalists were expelled from the government in the coup d'état of 18 Fructidor, year V (September 4, 1797), Pichegru was arrested and deported to French Guiana.

Escaping, Pichegru made his way to Germany, then to England. In January 1804 he secretly entered France and began plotting to overthrow Bonaparte's military regime. Arrested in Paris on February 28, he was found strangled with his cravat in Temple prison on April 5; it is not known whether he was murdered or committed suicide.