It has a western terminus at Nebraska Highway 92 in Arnold and an eastern terminus north of Kearney at an intersection with Nebraska Highway 10.

It goes south out of Arnold into farmland and at an intersection with Nebraska Highway 47, turns east.

It continues in a southeasterly direction through Eddyville and Sumner and at Miller, meets U.S. Highway 183.

It continues southeast through Amherst and Riverdale and ends north of Kearney at an intersection with Nebraska Highway 10.

Much of the alignment of Nebraska Highway 40 from Oconto southeastward to its eastern terminus lies parallel to the Wood River.