Duke of Medina Sidonia (Spanish: Duque de Medina Sidonia) is a peerage grandee title of Spain in Medina-Sidonia, holding the oldest extant dukedom in the kingdom, first awarded by King John I of Castile in 1380. His father, Henry II of Castile (c.1334-1379), had an illegitimate son named Enrique de Castilla y de Sousa with Juana de Sousa, but after being made a Duke by his half-brother in 1380, he died in 1404, without a successor. The title then returned to the Crown.

The title of Duke of Medina Sidonia was awarded a second time on February 1445 by King John II of Castile to Juan Alonso de Guzmán, 3rd Count of Niebla (1410-1468). They were once the most prominent magnate family of the Andalusian region, the best-known of whom, Don Alonso Pérez de Guzmán y Sotomayor, 7th Duke of Medina Sidonia, commanded the Spanish Armada at the end of the 16th century. The defeat at the hands of weather and the English in 1588 brought disgrace to this family. The House of Medina Sidonia traces its descent from Alonso Pérez de Guzmán (1265-1309).