Lerdo, orphaned and impoverished as a child, struggled to obtain an education and became professor of jurisprudence and rector of the College of San Ildefonso in Mexico City. A political liberal, he joined Benito Juárez during the period of French intervention in Mexico (1861–67), becoming president of the Tribunal Supremo (Supreme Court) and de facto vice president of the Mexican republic after its restoration in 1867.

After Juárez' death in 1872, Lerdo became president of Mexico, only to be immediately challenged by Porfirio Díaz (Díaz, Porfirio), another of Juárez' lieutenants. Opposed by provincial chieftains who resented Lerdo's increasingly centralized government, by the church for his connection with the anticlerical reforms of Juárez, and by progressives who criticized his failure to undertake public works, Lerdo was driven into exile by an uprising led by Díaz in 1877.