M-65 begins at an intersection with US 23 (Huron Road) near the town of Omer. The highway runs north along Hale Road through a mixed forest and agricultural area inland of the Saginaw Bay in Arenac County. As the road passes through the community of Twining, it crosses a branch of the Lake State Railway. South of Whittemore, the trunkline crosses a tributary of the Au Gres River. M-65 follows Bullock Street through Whittemore, running near the Whittemore Speedway in town. North of town, the highway crosses the main channel of the Au Gres River before it intersects M-55 in a rural area of Iosco County about west of Tawas City. From there, the road continues due north through fields until reaching the edge of Huron National Forest in the northern part of the county.