The Tribunal of the Holy Office of the Inquisition, commonly known as the Spanish Inquisition, was established in 1478 by the Catholic Monarchs, King Ferdinand II of Aragon and Queen Isabella I of Castile. It began toward the end of the Reconquista and was intended to maintain Catholic orthodoxy in their kingdoms and to replace the Medieval Inquisition, which was under papal control. It became the most substantive of the three different manifestations of the wider Catholic Inquisition, along with the Roman Inquisition and the Portuguese Inquisition. The "Spanish Inquisition" may be defined broadly as operating in Spain and in all Spanish colonies and territories, which included the Canary Islands, the Kingdom of Naples, and all Spanish possessions in North America and South America. According to some modern estimates, around 150,000 people were prosecuted for various offences during the three-century duration of the Spanish Inquisition, of whom between 3,000 and 5,000 were executed, approximately 2.7 percent of all cases. The Inquisition, however, since the creation of the American courts, has never had jurisdiction over the indigenous. The King of Spain ordered "that the inquisitors should never proceed against the Indians, but against the old Christians and their descendants and other persons against whom in these kingdoms of Spain it is customary to proceed".

Isabella I, also called Isabella the Catholic, was Queen of Castile and León from 1474 until her death in 1504. She was also Queen of Aragon from 1479 until her death as the wife of King Ferdinand II. Reigning together over a dynastically unified Spain, Isabella and Ferdinand are known as the Catholic Monarchs.