MD 650 serves as a major north-south commuter route in northwestern Prince George's County and eastern Montgomery County, connecting the District of Columbia with the residential suburbs of Takoma Park, Langley Park, Adelphi, Hillandale, White Oak, and Colesville.

By contrast, the part of MD 650 north of Spencerville is a quiet rural road connecting several small communities along the northeastern fringe of Montgomery County.

MD 650 was originally built between Takoma Park and Adelphi in the late 1930s as an extension of New Hampshire Avenue out of Washington.

Beginning in the 1950s and continuing through the 1990s, MD 650 has been expanded to a multi-lane divided highway in stages from its southern terminus north to Spencerville.

MD 650 continues into an area of apartment buildings and single family residences, then passes between a couple of shopping centers before intersecting MD 193 (University Boulevard) in Langley Park, where the Takoma Langley Crossroads Transit Center is located at the northwest corner of the intersection.

After passing more shopping centers and apartment complexes, the state highway crosses Northwest Branch and then immediately meets MD 320 at its eastern terminus.

MD 650 continues through apartment complexes and passes Metzerott Road on the east and Northampton Drive on the west, where the route enters Montgomery County for good.

After passing a shopping center on the right, the state highway reaches an intersection with the former National Labor College on the west and Powder Mill Road, which heads east toward MD 212.

The northbound direction gains a fourth lane ahead of passing the former Naval Ordnance Laboratory campus to the east, which is now the White Oak Federal Research Center occupied by the Food and Drug Administration.

[1][3] North of Spencerville, MD 650 becomes a two-lane road, passing several churches, subdivisions, and the Hampshire Greens Golf Course to the west.

[8] MD 320 continued north from its eastern terminus to the current intersection with Lockwood Drive in White Oak.

[8] From there, US 29 used Colesville Road through the namesake village up to Ashton, where the federal highway used the route of present-day MD 108 east to Ellicott City.