It enters Kentucky in the Todd County community of Guthrie, and leaves the state north of Henderson into Evansville.

[1] US 41 enters the state as a two-lane highway in Guthrie where it intersects US 79 and continues through Todd County through Trenton.

At US 60, US 41 becomes a four-lane surface road with stoplights as it crosses through the northern parts of Henderson and John James Audubon State Park.

Due to natural fluctuations of the Ohio River's path, US 41 remains in Kentucky for about one mile north of the Twin Bridges.

[5] In Hopkins County, US 41 previously followed the Pennyrile Parkway (much of which is now part of I-169 and I-69) between exits 30 and 45 until the early 1990s, when it was rerouted onto the former US 41 Alt.