West of Baltimore, in the Piedmont and Appalachian Mountains / Blue Ridge region of the Western Maryland panhandle of the small state, the portions where it does not overlap an Interstate highway are mostly two-lane roads.

From Cumberland on the western branch of the Potomac River and terminus of the historic Chesapeake and Ohio Canal, west to Pennsylvania, US 40 is the successor to the historic route of the National Road, first Federal interstate road built in the early 19th century which eventually ran from Baltimore west, through Ohio, Indiana, and Illinois to Vandalia, then territorial capital of the Illinois Territory near the Mississippi River.

US 40 continues southeast through sections of the Savage River State Forest and has a junction with MD 826H, at which point it curves east and passes businesses as a four-lane undivided road before intersecting the western terminus of US 40 Alt.

[1][3] Upon crossing Sideling Hill Creek, I-68/US 40 enters Washington County and curves northeast through forested areas, ascending a grade and coming to a westbound runaway truck ramp.

Just to the east of the cut is a pair of rest areas and the Sideling Hill Welcome Center along the westbound side of the road, with a pedestrian bridge providing access from the eastbound direction.

I-68 reaches its eastern terminus at a directional T interchange with I-70/US 522 near the town of Hancock, where US 40 continues east concurrent with I-70/US 522 on the Eisenhower Memorial Highway, a four-lane freeway.

The road comes to a westbound exit and eastbound entrance with the eastern terminus of the Hancock section of MD 144, where the median widens and it heads east through wooded areas with the Western Maryland Rail Trail, Chesapeake and Ohio Canal, and the Potomac River parallel to the south.

Past this interchange, the route intersects the northern terminus of MD 910 before it curves southeast and splits into the one-way pair of Washington Avenue eastbound and West Franklin Street westbound, carrying two lanes in each direction.

US 40 leaves downtown Hagerstown and the directions of the route rejoin as four-lane divided Dual Highway, intersecting the western terminus of MD 64 and passing a mix of homes and businesses.

Farther southeast, the road leaves the Middletown Valley and ascends forested Catoctin Mountain, passing south of Gambrill State Park and north of the community of Arch Bridge.

US 40 turns back to the east and widens to six lanes, passing south of the former Frederick Towne Mall as it continues through a commercial strip known as the "Golden Mile" before coming to a partial cloverleaf interchange with the US 15 freeway.

The freeway median narrows again as it curves southeast and comes to a partial cloverleaf interchange with Jefferson Street and the northern terminus of US 340, where US 15 splits from US 40 by heading southwest concurrent with US 340.

The freeway runs near suburban residential development and woodland, curving southeast and coming to a partial interchange with the eastern terminus of the Frederick section of MD 144 in Bartonsville, with no eastbound exit.

Past this interchange, US 40 turns northeast and passes more businesses, crossing Rogers Avenue before the eastbound side becomes paralleled by a service road that is designated MD 984.

The road heads into Catonsville, where it widens to six lanes and passes through a commercial strip of shopping centers and varieties of car dealerships and fast-food restaurants, curving to the east.

From here, the road heads east past commercial establishments and passes north of Edmondson-Westside High School and New Cathedral Cemetery before it continues into urban areas of rowhouses with some businesses.

After this, the road becomes a divided highway and runs through urban areas of homes and businesses in East Baltimore, heading south of Paul Laurence Dunbar High School before passing through the campus of The Johns Hopkins Hospital.

The route continues through industrial areas and passes under CSX's Baltimore Terminal Subdivision railroad line before it widens to a six-lane divided highway and reaches a partial cloverleaf interchange with MD 151 (Erdman Avenue) and the eastern terminus of US 40 Truck that also includes a ramp to southbound I-895 accessible from eastbound US 40.

US 40 comes to a cloverleaf interchange with I-695 (Baltimore Beltway), where it widens to six lanes, and heads southeast of The Centre at Golden Ring shopping center as it continues past businesses.

The road enters Middle River and passes near industrial parks, curving east to come to a bridge over CSX's Philadelphia Subdivision railroad line.

US 40 narrows to four lanes and continues northeast through a mix of wooded areas and commercial development, with the railroad tracks parallel a short distance to the northwest.

[1][3] Upon crossing Little Gunpowder Falls, US 40 enters Harford County and continues northeast along Pulaski Highway, with CSX's Philadelphia Subdivision parallel a short distance to the northwest.

The road runs past businesses before it heads through wooded areas between the closely parallel CSX line to the northwest and a branch of the Bush River to the southeast.

Past this interchange, US 40 leaves Aberdeen and runs through woodland with some development between CSX's Philadelphia Subdivision to the northwest and Amtrak's Northeast Corridor to the southeast.

The route intersects the eastern terminus of MD 132 and continues through business areas with some woods sandwiched between the two parallel railroad lines, passing the entrance to Bulle Rock Golf Course.

The route passes a pair of abandoned weigh stations as it runs through a mix of woods and sand quarries, with another section of MD 7 splitting to the southeast.

Past this intersection, the route heads into the town of Elkton and curves east-southeast, passing over Little Elk Creek and Amtrak's Northeast Corridor in a wooded area.

The route turns to the north-northeast and passes commercial development with some woodland, coming to a junction with the eastern terminus of a section of MD 7 that leads into the center of Elkton.

The long arches of the US 40 bridge over the upper / western branches of the Patapsco River in Ellicott City, originally constructed in 1936, were replaced in a project that started in the spring of 2011 and was expected to be completed in 2013.

[17] In June 1961, the Chadian ambassador to the U.S., Adam Malick Sow, was denied service by a white-owned diner by US 40 near Edgewood, which sparked an international incident and made headline news in Africa and Asia.