His sister, the Infanta Sancha of Castile, made a donation in July 1152 to construct a modest building on the outskirts of the walled city, on the banks of the Bernesga river, where "the poor of Christ" could stay.

During the course of the Spanish Civil War cells, rooms, stables, cloisters, church, choir, museum and every fast corner of the building were transformed into impromptu dungeons or jailers' offices, in what became officially known as "Campo de concentración de San Marcos" (San Marcos concentration camp).

It is estimated that, over the entire war and the period immediately following, the number of Republican militia members and political prisoners that passed through its cells totaled some 20,000.

In the sixteenth century, the medieval building was found to be in poor condition, so it was demolished and a new work was carried out thanks to a grant from Ferdinand the Catholic King in 1514.

In the following years, Orozco constructed the sculptures of the facade, the choir area was completed, and in 1549 Juan de Badajoz finished the sacristy.