Although his landowning family hoped he would enter the church, instead he joined Uruguayan military forces which in 1825 were fighting against Brazilian domination.
By 1830 he was a captain. After a short period as a civilian, he returned in 1832 to military action in support of President Fructuoso Rivera, who was then faced with an insurrection led by Juan Antonio Lavalleja.
In 1836 Flores escaped from prison, where he had been held by President Manuel Oribe of the Blanco Party. He joined Fructuoso Rivera’s revolt against Oribe and became commander in San José Department when Rivera’s forces triumphed. He supported Rivera’s war against Argentine tyrant Juan Manuel de Rosas, and for a short while was commander of Rivera's Colorado Party forces in Montevideo.
In 1851 Flores joined the Argentine Army of Justo José de Urquiza, which raised the nine-year long siege of Montevideo by forces supported by Rosas. In the following year, he served as minister of war and navy. After the overthrow of President Juan Francisco Giró, he became a member of a ruling three-man Junta, shortly afterward being elected constitutional president to (ill out Giro’s unexpired term. Although supported by a 4.000-man Brazilian Army, Flores was forced to resign in September 1853.
Joining forces with his old antagonist Manuel Oribe to put Gabriel Antonio Pereira in the presidency, Flores soon quarreled with Pereira and went to Argentina, where he spent several years as a rancher and a lieutenant of Bartolomé Mitre. He returned to Uruguay in April 1863 in order to lead a revolt against the Blanco Party government then in power. By early 1865 he had triumphed, with the support of Brazilian troops, and became president again.
Flores’ victory served as causus belli for the War of the Triple Alliance, when Paraguayan dictator Francisco Solano López came to the support of the Uruguayan Blancos and was faced with the forces of Argentina, Uruguay, and Brazil. Flores commanded the Uruguayan troops in that conflict until December 1866, when he returned to Montevideo. In the face of growing discontent, he allowed the calling of elections and then resigned in February 1868. Shortly afterward, he was assassinated.