The Señorío was created by order of King Sancho IV of Castile on 4 April 1295 and granted to Alfonso Pérez de Guzmán el Bueno for services rendered to the Castilian crown, specifically, his heroic defence of Tarifa during the Spanish Reconquista.

Although Sancho IV died before handing over control officially to Guzmán el Bueno, his son, Ferdinand IV of Castile confirmed the handover to Guzmán as follows La Villa de Sanlúcar con todos sus pobladores, términos y pertenencias, y los pechos y derechos que allí tenía y deber había (En: The Lordship of the town of Sanlúcar with all its people, income and belongings and the rights which this land held and should hold).

Trebujena was made into an independent town chartae populationis on 21 April 1494 by order of Juan Alonso Pérez de Guzmán y de Ribera, the III Duke of Medina Sidonia.

The Señorío de Sanlúcar was the power base of the House of Medina Sidonia until 1645 when Sanlúcar de Barrameda was incorporated into the Spanish crown.

This occurred in the aftermath of the Andalusian independentist conspiracy, an effort by the House of Medina Sidonia to consolidate power at the expense of the Spanish crown.