In 1631, Sir Ferdinando Gorges, who first attempted to colonize Maine, gifted the island to Arthur Mackworth, his deputy in Casco Bay, and the island has retained his name.

[3] A causeway, which carries the traffic of Andrews Avenue, connects the island to Mackworth Point on the mainland.

Visitors to the island must pass a state park entrance tollhouse and pay an entrance fee; cars can enter the island, but parking is limited.

The island is also home to the Governor Baxter Dog Memorial, a pet cemetery where fourteen of the former governor's Irish Setters and one of his horses were buried, accompanied by two bronze markers and a gravestone, all enclosed by a circular stone wall.

Friends School of Portland, an independent Quaker preschool through eighth grade school, was located on Mackworth Island from 2006 to 2015, when it moved to new facility in nearby Cumberland, Maine.