It is the headquarters of the oldest penitential brotherhood of Holy Week in Valladolid, originally associated with the care of contagious patients. The members of the brotherhood commissioned the construction to Pedro de Mazuecos in 1581, who was obliged to respect and preserve the arch that existed at the end of Platerías Street on the façade.

Its current appearance is not its original one, as the church has undergone interventions such as the addition of a balcony to the façade by the prestigious Diego de Praves around 1595, as well as a nave expansion in the 17th century.

The Church of La Vera Cruz came close to disappearing on several occasions: in 1806, due to a fire; in 1936, when the City Council approved a project for Gran Vía that was never carried out; and in 1938, due to a new urban project that proposed its demolition. Fortunately, none of these plans were executed, as the view it offers from the entrance of Platerías Street creates a picturesque scene worthy of being photographed.

It houses a valuable collection of altarpieces and wooden sculptures, including those created by Gregorio Fernández, as well as a 16th-century wooden and papier-mâché float depicting "La Borriquilla." Its most emblematic symbol is the Cross of May, which carries a relic of the True Cross, and is paraded every 3rd of May.