The purpose of the hospital was to alleviate the pitiful situation of elderly clergymen, the sick, the disabled and vagrants at a time of general decline, famine and hardship, largely caused by a serious outbreak of the plague in 1649. Pedro Manuel de Colón y Portugal, Duke of Veragua, Count of Gelves and a descendent of Christopher Columbus, donated a plot of land on which to build the hospital in the Santa Cruz quarter. It included what had formerly been the Doña Elvira courtyard theatre, to which rows of houses were added in Callejón del Agua and Plaza Atambor.

Work began on the construction of the hospital in 1676 under the direction of the master architect Juan Domínguez. The work was later continued until its completion in 1698 by Leonardo de Figueroa, who was one of the leading figures of Baroque architecture in Seville, responsible for the church of San Pablo and involved in the construction of the church of El Salvador and San Telmo Palace. The hospital was built with alms requested by members of the Los Venerables Sacerdotes brotherhood, donations and the rent from properties belonging to the brotherhood. The brothers themselves often stood on the steps of the cathedral collecting alms to contribute to the funds for the hospital. On several occasions, construction work came to standstill, awaiting significant donations by such people as the archbishops of the city, Ambrosio Ignacio Espínola y Guzmán and Jaime Palafox, which would enable the work to continue. Juan Valdés Leal and his son, Lucas Valdés, Bartolomé E. Murillo, Pedro Roldán and other artists and craftsmen of the time contributed to the construction and decoration of the building, whose church was dedicated to the King Saint Ferdinand, who was canonized at that time. The Hospital de los Venerables Sacerdotes was run for almost three hundred years according to a set of rules for the destitute clergymen who were taken in, established at the end of the 17th century. The institution continued through to present times, although it was subject to many ups and downs. The disentailment of properties in the 19th century meant that it was used on different occasions as a storehouse, a textile factory and a match factory. It stopped carrying out its social functions in 1960, and the building fell into a state of decay. Then, on 9 July 1987 Focus-Abengoa signed a contract with the Archbishop of Seville and the Los Venerables Sacerdotes brotherhood, giving the building to the Foundation in trust for a limited period of time. The agreement established certain conditions, mainly relating to the restoration and renovation of the fabric of the building and ensuring that the people of city would not be deprived of the chance to enjoy its church, its courtyard and its artistic heritage. The main entrance to the building located in the square called Plaza de los Venerables is through a sober porch, leading to a spacious entrance hall with a modest staircase to the main courtyard. On the right-hand side of the entrance hall, there is a wrought iron gate affording access to what was the administrator's house, built around a small courtyard and one of the best examples of Sevillian domestic architecture of the time. The building is an amalgamation of convent and Sevillian mansion with a striking combination of contrasting whitewashed walls and red brick that creates a very distinct, expressive chromatic impact in the central courtyard, a beautiful square-shaped area surrounded by an open arcade on the ground floor and French windows on the upper story.

	The focal point of the courtyard is a sunken fountain encircled by concentric brick and tile steps that create a beautiful effect. The rooms and the church are arranged in a harmonious manner around the courtyard. The ground floor was formerly occupied by the chapter house, the summer dining room and the downstairs infirmary, now an exhibition hall. The spacious rectangular room is divided into two areas by columns supporting arches and a simple coffered ceiling. An elegant main stairway connects the central courtyard to the second body of the building, which is covered by a vault richly stuccoed in the Baroque style featuring beautiful plant-inspired plasterwork. The second floor used to house the refectory, the winter chapter house and the cells, an area that has now been converted into an exhibition hall, the library, the Collection of Engravings room and the conference room. What was formerly the basement or cellar has been refurbished as a third exhibition room connected to the others by lift.
The main façade of the church gives onto Calle Jamerdana. The only church in Seville dedicated to St Ferdinand, it has a typically local layout, featuring a single wide, rectangular-shaped nave and a dome-covered transept. Its walls were decorated by Juan de Valdés Leal and his son Lucas Valdés, and the altarpieces were hung with paintings by Murillo, including The Immaculate Conception of Soult or Los Venerables, now in the Prado Museum in Madrid, The Penitent St Peter, now part of the Townsend Collection in Newick, and The Infant Jesus Distributing Bread to Pilgrims, now in the Museum of Fine Arts in Budapest.
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