Western Mindanao is named after the Maguindanaons who constituted the largest Sultanate historically, and evidence from maps made during the 17th and 18th centuries suggests that the name was used to refer to the island by natives at the time. Evidence of human occupation dates back tens of thousands of years. In prehistoric times the Negrito people arrived. Sometime around 1500 BC Austronesian peoples spread throughout the Philippines and far beyond.

Islam first spread to the region during the 13th century through Arab traders from present-dayMalaysia and Indonesia. Prior to this contact, the inhabitants of the area were primarily animists living in small autonomous communities. The indigenous population was quickly converted and the firstmosque in the Philippines was built in the mid 14th century in the town of Simunul. The Philippine sultanates of Sulu and Maguindanao were subsequently in the 15th and 16th centuries, respectively. In the late 16th to early 17th centuries, the first contact with Spain occurred. By this time, Islam was well established in Mindanao and had started influencing groups as far north as present-day Manila on the island of Luzon.

Upon the Spaniards' arrival to the Philippines, they were dismayed to find such a strong Muslim presence on the island, having just expelled theMoors from Spain after centuries of fighting. In fact, the name Moros (the Spanish word for "Moors") was given to the Muslim inhabitants by the Spanish. Caesarea Caroli was the name given by Villalobos to the island of Mindanao when he reached the sea near it. This was named after the Charles V of the Holy Roman Empire (and I of Spain).

The region is home to most of the country's Muslim or Moro populations, composed of many ethnic groups such as the Maranao and the Tausug, theBanguingui (users of the vinta), as well as the collective group of indigenous tribes known as the Lumad.

At the beginning of the 20th century, the Lumads controlled an area which now covers 17 of Mindanao’s 24 provinces, but by the 1980 census, they constituted less than 6% of the population of Mindanao and Sulu. Heavy migration to Mindanao of Visayans, spurred by government-sponsored resettlement programmes, turned the indigenous Lumads and Moros into minorities