Manuel María was born on 18 June 1808 in Santiago de Cali, then part of the Viceroyalty of New Granada, the oldest child of José María Mallarino y Vargas, a Spaniard natural of Cádiz of Italian descent, and Juana María de la Concepción Ibargüen (née Scarpetta Roo y Bedoya), a Criolla natural of Cali also of Italian descent.

[2] His nephews Carlos and Jorge Holguín Mallarino, sons of his sister María Josefa, became prominent Conservative party politicians who like him served in Congress and as Acting Presidents; Jorge went on to serve as the 10th President of Colombia.

Mallarino served as the 21st, 23rd, and 25th Secretary of Foreign Affairs of New Granada during the Administration of President Tomás Cipriano de Mosquera y Arboleda.

In 1861 Mallarino was tapped again to serve as Secretary of Foreign Affairs, this time appointed by President Bartolomé Calvo Díaz during the Civil War of 1860–1862.

For this reason when Mallarino took office on 1 April 1861 as the 2nd Secretary of Foreign Affairs of the Granadine Confederation he only served until 10 July,[4] when General Mosquera, under whose Administration he had served as Secretary of Foreign Affairs in the past, deposed President Calvo and toppled the Government.