The N16 begins at the junction of the N15 at Cartron, Sligo, and travels northeast, past the Institute of Technology, Sligo and onwards, passing above Glencar Lake and entering County Leitrim.

The route continues to Enniskillen and further east towards Belfast as the A4 and the M1 Motorway.

Compared with many other national primary roads in Ireland, long sections of the N16 are narrow and twisty which can make travelling on it slow and difficult.

In recent years improvements have been made to short sections of it but the geography of many of the areas it passes through (deep valleys and steep hills) places some limits on the improvements that can be made without a wholesale realignment of parts of the route (i.e., finding less difficult terrain nearby to build a new road through).

[citation needed] As of December 2019, upgrades to further sections of the N16 were planned.