Much of what is now MD 346 was built as the original state road between Salisbury and Ocean City in the mid-1910s.

Main Street continues west into downtown Salisbury on the other side of US 50 Business.

MD 346 heads northeast as Main Street, a two-lane undivided road maintained by the city of Salisbury.

MD 346 passes under the Salisbury Bypass (US 13 and US 50) without access and continues east through a mix of farmland and scattered residences, crossing Beaverdam Creek.

Upon entering the town limits of Berlin, the state highway curves east to intersect MD 818 (Main Street).

MD 346 has a grade crossing of the Maryland and Delaware Railroad's Snow Hill Line track, then intersects the northern terminus of MD 377 (Williams Street) immediately before an intersection with US 113 (Worcester Highway).

The state highway passes south of Atlantic General Hospital and veers northeast to its eastern terminus at a tangent intersection with US 50.