SR 16 runs from the New Hampshire state line (signed as NH-16) at Wentworth Location (near Lake Aziscohos) in the west to Orono at the eastern terminus.

State Route 16 runs a total of 190 miles (310 km), passing mostly through rural areas, with the largest population center at its eastern terminus in Orono at Interstate 95 (I-95).

As originally designated, SR 16 crossed the state from Haines Landing to New Brunswick.

It then takes a northwards jog parallelling US 201 before crossing it in Bingham and turning eastwards.

This eastwards direction continues until the route reaches Milo, where it turns southward once again to its terminus in Orono.