Tradition has it that it was built on the site where the house belonging to San Isidro and his wife, Santa María de la Cabeza, was located. After his death, San Isidro’s body was kept in the church of San Andrés until Pope Leo X granted its custody to the Vargas family in 1518. They later placed it in the Bishop’s Chapel next door to San Andrés church.

Work on the Chapel of San Isidro began on 12 April 1657 in the presence of King Philip IV and his wife, Mariana of Austria, and it was solemnly opened on 15 May 1699. The structure is a magnificent example of Baroque architecture. The first project presented by Juan Gómez de Mora in 1629 was discarded, and work on it began in 1642 following the plans prepared by Pedro de la Torre.

Built next to the San Andrés Church, the chapel is a building in its own right; it was constructed following an elongated floor plan (perpendicular to the church) and has a faux vault dome, topped by a lantern. Pedro de la Torre was followed by José de Villareal, who continued the chapel’s construction in 1657, and later by Juan de Lobera, who finished off the work in 1669.

The saint’s body continued to be venerated in the San Isidro Chapel until the expulsion of the Society of Jesus in 1769, following which his remains were transferred to the church at the Imperial College on Calle Toledo. Ever since then it has been known as the Colegiata de San Isidro. On 18 July 1936, shortly after the outbreak of the Spanish Civil War, the chapel and church were burnt down and were totally destroyed. After the war, the building was completely rebuilt, and its restoration continued until 1991.