Oribe's siege of Montevideo marked the beginning of the Great War (Guerra Grande, 1843-52). The Great War centered on the nineyear -long siege of Montevideo, described by Alexandre Dumas as a "new Troy," although the city itself suffered relatively little from the war. Britain had saved Montevideo at the outset by allowing the city to receive supplies. During the Great War, there were two governments in Uruguay: the Colorados at Montevideo (the so-called government of the "defense") and the Blancos at Cerrito (Little Hill), a promontory near Montevideo.

The intervention first of France (1838-42) and then of Britain and France (1843-50) transformed the conflict into an international war. First, British and French naval forces temporarily blockaded the port of Buenos Aires in December 1845. Then, the British and French fleets protected Montevideo at sea. French and Italian legionnaires (the latter led by Giuseppe Garibaldi) participated, along with the Colorados, in the defense of the city.

Historians believe that the reason for the French and British intervention in the conflict was to restore normalcy to commerce in the region and to ensure free navigation along the Río Paraná and Río Uruguay, thus guaranteeing access to provincial markets without Buenos Aires's interference. Their efforts were ineffective, however, and by 1849 the two European powers had tired of the war. In 1850 both withdrew after signing a treaty that represented a triumph for Rosas of Argentina.

It appeared that Montevideo would finally fall. But an uprising against Rosas led by Justo José de Urquiza, governor of Argentina's Entre Ríos Province, with the assistance of a small Uruguayan force, changed the situation. They defeated Oribe in 1851, thereby ending the armed conflict in Uruguayan territory and leaving the Colorados in full control of the country. Brazil then intervened in Uruguay in May 1851 on behalf of the besieged Colorados, supporting them with money and naval forces. With Rosas's fall from power in Argentina in February 1852, the siege of Montevideo was lifted by Urquiza's pro-Colorado forces.

Montevideo rewarded Brazil's vital financial and military support by signing five treaties in 1851 that provided for perpetual alliance between the two countries, confirming Brazil's right to intervene in Uruguay's internal affairs; extradition of runaway slaves and criminals from Uruguay (during the war, both the Blancos and the Colorados had abolished slavery in Uruguay in order to mobilize the former slaves to reinforce their respective military forces); joint navigation on the Río Uruguay and its tributaries; tax exemption on cattle and salted meat exports (the cattle industry was devastated by the war); acknowledgment of debt to Brazil for aid against the Blancos; and Brazil's commitment for granting an additional loan. Borders were also recognized, whereby Uruguay renounced its territorial claims north of the Río Cuareim (thereby reducing its boundaries to about 176,000 kilometers) and recognized Brazil's exclusive right of navigation in the Laguna Merín and the Río Yaguarón, the natural border between the countries.