On May 14, 1845, he married Modesta García de Cossio y Vedoya Lagraña (1825–1885) with whom he had three boys (Manuel Santiago, Simón, and Santiago Martín Antonio) and three girls (Josefa, Justa Dolores Belisaria, and María del Carmen Modesta Leonor).

Justo José de Urquiza named him 'Business administrator' and sent him to Paraguay on a foreign business mission.

Derqui accepted the revised national constitution with the changes that would favour Buenos Aires, and named the country República Argentina.

This and other unpopular policies towards the rest of the country provoked a general discontent in the provinces that led to the Battle of Pavón.

While in exile, Bartolomé Mitre helped him to go back to his wife's native city of Corrientes, where he would die a few years later.