SR 281 does not pass through any incorporated villages through Henry County, but it intersects State Routes 108, 109, and 65.

After crossing into Wood County, SR 281 enters the small village of Custar.

[13] In 1972, SR 281 was extended west on a new bridge over the Maumee River and over existing roads to end at the US 24 bypass of Defiance and Napoleon.

[14][15] The road between CR 424 (formerly SR 424) and US 24 had been designated as a part of US 24 during the time the Defiance bypass was complete but the Napoleon portion was still under construction.

[16][17] The at-grade intersection with US 24 was replaced by a diamond interchange in 2007 as a part of the widening of US 24 through northwestern Ohio.