End of the Uruguayan War, with a peace agreement between President Tomás Villalba and rebel leader Venancio Flores, setting the scene for the destructive War of the Triple Alliance.

The Paraguayan War, also known as the War of the Triple Alliance, was a South American war that lasted from 1864 to 1870. This war was fought between Paraguay and the Triple Alliance of Argentina, the Empire of Brazil, and Uruguay. It was the deadliest and bloodiest inter-state war in Latin American history. Paraguay sustained large casualties, but even the approximate numbers are disputed. Paraguay was forced to cede disputed territory to Argentina and Brazil. The war began in late 1864, as a result of a conflict between Paraguay and Brazil caused by the Uruguayan War. Argentina and Uruguay entered the war against Paraguay in 1865, and it then became known as the "War of the Triple Alliance".

After Paraguay was defeated in conventional warfare, it conducted a drawn-out guerrilla resistance, a strategy that resulted in the further destruction of the Paraguayan military and the civilian population. Much of the civilian population lost their lives due to battle, hunger, and disease. The guerrilla war lasted for 14 months until President Francisco Solano Lpez was killed in action by Brazilian forces in the Battle of Cerro Cor on 1 March 1870. Argentine and Brazilian troops occupied Paraguay until 1876.

The Uruguayan War (10 August 1864 – 20 February 1865) was fought between Uruguay's governing Blanco Party and an alliance consisting of the Empire of Brazil and the Uruguayan Colorado Party, covertly supported by Argentina. Since its independence, Uruguay had been ravaged by intermittent struggles between the Colorado and Blanco factions, each attempting to seize and maintain power in turn. The Colorado leader Venancio Flores launched the Liberating Crusade in 1863, an insurrection aimed at toppling Bernardo Berro, who presided over a Colorado–Blanco coalition (fusionist) government. Flores was aided by Argentina, whose president Bartolomé Mitre provided him with supplies, Argentine volunteers and river transport for troops.

The fusionism movement collapsed as the Colorados abandoned the coalition to join Flores' ranks. The Uruguayan Civil War quickly escalated, developing into a crisis of international scope that destabilized the entire region. Even before the Colorado rebellion, the Blancos within fusionism had sought an alliance with Paraguayan dictator Francisco Solano López. Berro's now purely Blanco government also received support from Argentine federalists, who opposed Mitre and his Unitarians. The situation deteriorated as the Empire of Brazil was drawn into the conflict. Almost one fifth of the Uruguayan population were considered Brazilian. Some joined Flores' rebellion, spurred by discontent with Blanco government policies that they regarded as harmful to their interests. Brazil eventually decided to intervene in the Uruguayan affair to reestablish the security of its southern frontiers and its regional ascendancy.

In April 1864, Brazil sent Minister Plenipotentiary José Antônio Saraiva to negotiate with Atanasio Aguirre, who had succeeded Berro in Uruguay. Saraiva made an initial attempt to settle the dispute between Blancos and Colorados. Faced with Aguirre's intransigence regarding Flores' demands, the Brazilian diplomat abandoned the effort and sided with the Colorados. On 10 August 1864, after a Brazilian ultimatum was refused, Saraiva declared that Brazil's military would begin exacting reprisals. Brazil declined to acknowledge a formal state of war, and for most of its duration, the Uruguayan–Brazilian armed conflict was an undeclared war.

In a combined offensive against Blanco strongholds, the Brazilian–Colorado troops advanced through Uruguayan territory, taking one town after another. Eventually the Blancos were left isolated in Montevideo, the national capital. Faced with certain defeat, the Blanco government capitulated on 20 February 1865. The short-lived war would have been regarded as an outstanding success for Brazilian and Argentine interests, had Paraguayan intervention in support of the Blancos (with attacks upon Brazilian and Argentine provinces) not led to the long and costly Paraguayan War.