The island was first inhabited by Native American tribes, including the Potawatomi, who used the island for fishing and hunting. They named the island "Kendawawido" or "Island of the Long Knives".
In the 1800s, European settlers began to arrive on the island, which was then part of Macomb County. The first European settler was Charles Harsen, who purchased the island in 1816 and gave it its current name.
Fishing and shipping became major industries on the island, with fishermen catching whitefish, perch, and other fish from the surrounding waters. The island was also an important stop for steamships traveling between Detroit and Port Huron.
During Prohibition in the 1920s, Harsens Island became a center for bootlegging, with smugglers using the island's many inlets and marshes to hide their illegal activities.
After World War II, the island became a popular spot for vacation homes and cottages, as people sought to escape the city and enjoy the natural beauty of the island.
In 1953, the Michigan Department of Natural Resources established the Harsens Island Wildlife Refuge on the island, which covers over 1,200 acres and is home to a variety of birds and other wildlife.