Maryland Route 12 heads north from the Virginia border on Snow Hill Road, which is a two-lane undivided road. The road continues south into Virginia as State Route 679 (Fleming Road). From the border, the route passes through a mix of woodland and farmland with a few residences in southern Worcester County before reaching Stockton. Here, MD 12 passes by homes and crosses Maryland Route 366 (George Island Landing Road). Upon leaving Stockton, the roads heads back into rural areas and passes near the E.A. Vaughn Wildlife Management Area before reaching the residential community of Girdletree. Past Girdletree, the road continues to the east of a tract of the Pocomoke State Forest as it approaches Snow Hill, the county seat of Worcester County. Just south of Snow Hill, the route intersects U.S. Route 113 (Worcester Highway).
Past this intersection, the road enters Snow Hill, where it becomes Church Street, and heads into inhabited areas with some businesses. In the center of town, MD 12 intersects U.S. Route 113 Business (Market Street) and turns east to form a concurrency with that route, passing through the downtown area. Within the downtown, the road passes by the Julia A. Purnell Museum and the Worcester County Courthouse. Here, MD 12 turns north to follow Washington Street, crossing the Pocomoke River out of downtown Snow Hill on a drawbridge. From here, the route becomes Snow Hill Road again and turns northwest. The road heads into agricultural areas with some residences before Indiantown, where MD 12 intersects the southern terminus of Maryland Route 354 (Whiton Road), which runs north to Willards. Past this intersection, the route turns more to the west and heads through a mix of farmland and woodland with occasional homes. The road turns to the northwest again and runs to the northeast of more tracts of the Pocomoke State Forest. The Pocomoke State Forest is known for its loblolly trees and cypress swamps and is popular with fishing and hunting.
Northbound MD 12 at intersection with College Avenue/Beaglin Park Drive in Salisbury.
MD 12 crosses into Wicomico County, where it continues north through woods and farms with some residences. The route turns northwest again before heading into a mix of residential areas and farm fields on the outskirts of Salisbury. The road comes to a partial cloverleaf interchange with U.S. Route 13 (Salisbury Bypass), where the route briefly becomes a four-lane divided highway . Past US 13, MD 12 crosses into Salisbury at the Johnson Road intersection. Here, the route heads north through commercial areas, becoming a six-lane road with a center left-turn lane, two southbound travel lanes and one northbound travel lane. In addition, there is one lane in each direction devoted to right turns. At the intersection with College Avenue/Beaglin Park Drive, the road narrows to four-lane with each direction consisting of one travel lane and a right-turn lane. This configuration eventually ends and MD 12 becomes a two-lane road again, leaving the corporate limits of Salisbury. Upon entering Salisbury again, the route becomes municipally maintained and continues past a mix of residences and businesses with some industrial establishments. MD 12 crosses over a branch of the Wicomico River near the Salisbury city park, which contains the Salisbury Zoo, before ending at Main Street a short distance to the east of U.S. Route 13 Business (Salisbury Boulevard) near downtown Salisbury.
The portion of MD 12 south of Snow Hill was part of an old post road from the 18th century that ran the length of the Delmarva Peninsula. The section of the state highway north of Snow Hill is the descendant of the Old Snow Hill Road from Salisbury whose original bridge across the Pocomoke River dates to 1878. The Maryland State Roads Commission designated the highway from Stockton to Snow Hill as one of the original state roads in 1909. By 1910, the highway was paved within Stockton, between Snow Hill and Indiantown, and for about 2 miles (3.2 km) south from the city limit of Salisbury. The highway was paved from Snow Hill to a point north of Girdletree by 1917. The all-weather road between Snow Hill and Stockton was completed by 1921. The Snow Hill–Salisbury road was under construction by 1923. By 1927, MD 12 had been assigned to the highway despite a 4-mile (6.4 km) gap remaining from just north of the Wicomico–Worcester county line south toward Snow Hill. That gap was filled by 1930. In addition, MD 12's present northern terminus at Main Street, including the bridge across the South Prong of the Wicomico River, was constructed in 1928 and 1929. The highway had previously entered Salisbury along Lincoln Avenue and Division Street. The final portion of MD 12 was completed between Stockton and the Virginia state line by 1933. In addition, the present bridge across the Pocomoke River was completed in 1932. MD 12 was widened and straightened from Stockton to Salisbury between 1951 and 1954.
An interchange is planned between MD 12 and US 113 south of Snow Hill in order to improve safety and traffic flow as a follow up to widening US 113; however, the project is currently on hold. This proposed interchange is to be a dumbbell interchange, a variation of the diamond interchange with two roundabouts on MD 12 where it intersects the ramps to US 113. The proposed cost needed to build this interchange is $24.2 million, which includes engineering, acquisition of land, and the actual construction.