After a long time in exile, he returned to the country after the fall of the Rosas' regime, and acted as Senator for San Luis Province.
In 1856, he was designated commander of the frontier armed forces, and in 1859 he was elected Governor of San Luis, and fought at the Battle of Cepeda that same year.
He then was elected Vice-President to President of the Argentine Confederation Santiago Derqui, and served from 1860 until 1861, when Derqui resigned after the Battle of PavĂłn.
Pedernera then acted as President until the political situation forced the dissolution of the office.
In 1882 he was designated Lieutenant General of the Armies of the Republic.