The state highway heads north as a two-lane undivided road through the village of Nanticoke.

The state highway intersects the west end of MD 352 (Capitola Road), then turns northeast past the Chesapeake Forest Lands and traverses Wetipquin Creek.

Upon crossing Mitchell Pond, MD 349 enters the city of Salisbury and municipal maintenance begins.

Main Street splits to the southeast from the eastbound direction of MD 349 immediately before the state highway reaches its eastern terminus at US 50 Business (Salisbury Parkway).

[1][2] MD 349 is a part of the National Highway System as a principal arterial from Fire Tower Road near Quantico to its eastern terminus in Salisbury.