The area of the city was originally inhabited by Comechingón aboriginals, which were thoroughly displaced or exterminated by the Spanish conquistadores by the end of the 17th century.

The first official owner of the lands was Francisco de Baigorri, as recorded on September 22, 1735, which is taken as the foundation date of the city.

The settlement was linked by a road to the provincial capital, Córdoba, in 1878, and it was declared a municipality on May 8, 1890; at the time it had about 4,000 inhabitants.

Cruz del Eje's position as a railroad node would lead to a rapid growth in importance; the railway workshops were dismantled in the 1970s.

The Cruz del Eje Reservoir, initiated by Governor Amadeo Sabattini, was completed in 1943.