The island is 18 miles (29 km) long, stretching from Corpus Christi to Port Aransas.

The island is oriented generally northeast–southwest, with the Gulf of Mexico on the east and south, and Corpus Christi Bay on the north and west.

In 1519, when Spanish explorer Alonso Álvarez de Pineda sailed through the pass to what he later named Corpus Christi Bay, the island was inhabited by the Karankawa people.

The pirate Jean Lafitte purportedly frequented Mustang and neighboring islands during the 1820s.

During the Mexican–American War, a small fort was built on the island to defend the entrance to Aransas Bay.