Founded by Dominican friars in 1542, Santo Domingo became the biggest and richest monastery in Antigua. Following three 18th-century earthquakes, the buildings were pillaged for construction material. The site was acquired as a private residence in 1970 by a North American archaeologist, who performed extensive excavations before it was taken over by the Casa Santo Domingo Hotel.

The archaeological zone has been innovatively restored as a 'cultural route.' It includes the picturesque ruined monastery church, the adjacent cloister with a replica of the original fountain, workshops for candle and pottery makers, and two underground crypts that were discovered during the church excavations. One of these, the Calvary Crypt, contains a well-preserved mural of the Crucifixion dating from 1683.

Also part of the archaeological zone are six museums, which can all be visited with one admission ticket. This museum route may be entered either through the hotel or the Universidad de San Carlos extension on 1a Av Norte. Starting from the hotel side, the route includes the following museums: the Museo de la Platería, with silver-work masterpieces including incense burners, candelabras and crowns; the Museo Colonial, with canvases and wood sculpture on religious themes from the 16th to 18th centuries; the Museo Arqueológico, with ceramic and stone objects from the Maya Classic period; the Museo de Arte Precolombino y Vidrio Moderno, with glass works by modern artists and the pre-Hispanic ceramic pieces that inspired them; the Museo de Artes y Artesanías Populares de Sacatepéquez, with exhibits on traditional handicrafts from the Antigua region; and the Museo de la Farmacia, a restored version of a 19th-century apothecary's shop from Guatemala City.

A recently added component to the complex is a cultural park upon Cerro Santa Inés, a hill located 1km to the southeast of the monastery complex. Aside from stunning views of Antigua and Volcán Agua, Santo Domingo del Cerro offers a museum devoted to artist Efraín Recinos, whose murals and sculptures (including one featuring his VW bug) grace the gardens. Another small museum covers Pope John Paul II's 2002 visit to Guatemala. A free shuttle service runs from the hotel to Santo Domingo del Cerro every 15 minutes.