The state road runs through seven counties in northern Indiana mostly through rural farm fields and small towns.

SR 16 begins at US 41 at an intersection in rural Newton County, just east of Ade.

[1][3][4] In White County SR 16 crosses over a CSX railroad track before entering Monon.

SR 16 leaves Monon passing through agricultural land in rural White County.

The road makes a sharp curve to become north–south before a four-way intersection with SR 39 and 900 North.

In Buffalo the concurrency turns south and crosses over Tippecanoe River.

[1][3][4] In Cass County SR 16 passes through Royal Center and an intersection with US 35.

The SR 16 designation ends at an intersection with SR 5 in rural Huntington County, northwest of the city of Huntington, while the roadway continues east as a county road.

[10][11] Between late 1932 and early 1933 SR 16 between Huntington and Markle was under construction as a high type road surface.

[11][12] US 224 replaced SR 16, between Huntington and the Ohio state line, between 1933 and 1934.