In the early 19th century when the first white settlers arrived in Southeastern Wisconsin, the Potawatomi and Menominee Native Americans inhabited the land now occupied by the Town of Wayne.

[3][4] While many Native people moved west of the Mississippi River to Kansas, some chose to remain, and were referred to as "strolling Potawatomi" in contemporary documents because many of them were migrants who subsisted by squatting on their ancestral lands, which were now owned by white settlers.

Eventually the Native people who evaded forced removal gathered in northern Wisconsin, where they formed the Forest County Potawatomi Community.

[5] The first white settlers arrived in 1846,[6] when the land was part of the Town of Addison and largely covered with dense hardwood forests.

Unlike neighboring towns, Wayne never had any railroad connections, and the hamlets of Kohlsville, St. Kilians, and Wayne Center remained rural communities that served the local farmers, unlike hamlets in neighboring towns which grew and prospered with construction of new railroads.

[7] According to the United States Census Bureau, the town has a total area of 35.8 square miles (92.7 km2), all of it land.