A short separate piece crosses northern Loudoun County on its way from West Virginia to Maryland.

It is the main route between Charles Town and Harpers Ferry, and it is known as the William L. Wilson Freeway through that stretch.

The U.S. highway also links Frederick with Harpers Ferry and Charles Town in the Eastern Panhandle of West Virginia.

The modern US 340 Bridge was constructed at Sandy Hook between 1940 and 1947, with a long interruption due to World War II.

The U.S. highway is part of the main system from Virginia State Route 7 (SR 7) near Berryville to its northern terminus in Frederick.

[4][5][6][7] US 340 is a National Highway System principal arterial from I-64 to its eastern junction with US 250 in Waynesboro, along its US 211 concurrency near Luray, and from US 522 to I-66 in Front Royal.

[4][5][6] US 340 begins at an intersection with US 11 (Lee Highway) on the northern edge of Greenville and just east of US 11's interchange with I-64 and I-81 in southern Augusta County.

US 340 expands to a five-lane road with center turn lane west of the village of Stuarts Draft.

US 340 passes through the hamlet of Ladd before leaving Augusta County and entering the independent city of Waynesboro at its partial cloverleaf interchange with I-64.

The two highways run concurrently east along four-lane Main Street and under Norfolk Southern Railway's Roanoke District rail line to Delphine Avenue, onto which US 340 turns north.

US 340 passes the General Electric Specialty Control Plant and parallels the Norfolk Southern rail line north out of the city and back into Augusta County.

[1][9] US 340 continues north as East Side Highway, which parallels the South River and the rail line along the flank of the Blue Ridge Mountains along the eastern edge of the Shenandoah Valley.

The highway follows Augusta Avenue through the east side of the town and meets the eastern end of SR 256 (Third Street).

The highway passes to the south of the historic estate Bogota and by a monument to the Battle of Port Republic at Lynnwood.

[1][9] US 340 continues northeast as two-lane Stonewall Jackson Memorial Highway through the communities of Springfield, Big Spring, and Oak Hill.

The highway continues through Bentonville, the site of Shenandoah River Raymond R. "Andy" Guest Jr. State Park.

The two highways pass the Warren County Courthouse at the west end of the Front Royal Historic District.

US 340 and US 522 diverge at a four-legged intersection at Double Tollgate, from which US 522 continues north toward Winchester; the west leg of the junction is SR 277 (Fairfax Pike), which heads toward Stephens City.

[1][9] The highway, named Berryville Pike, passes by Ripon Lodge in Rippon and near the William Grubb Farm near Wheatland.

The U.S. Highway passes along the southern and eastern fringes of the city and has a partial interchange with WV 115, which heads toward downtown along George Street and east on Charles Town Road.

[11] The U.S. Highway passes to the north of Rion Hall, crosses over CSX's Shenandoah Subdivision rail line, and meets the southern end of WV 230 (Shepherdstown Pike) at Halltown.

US 340 has its sole intersection in its second run through Virginia with SR 671 (Harpers Ferry Road) in Loudoun Heights.

[1][9] The route then crosses the Potomac River into Washington County, Maryland, on a southwest–northeast angle on a two-lane steel continuous deck truss bridge that passes above Chesapeake and Ohio Canal National Historical Park, CSX's Cumberland Subdivision rail line, and Sandy Hook Road.

US 340 expands to a four-lane freeway at the community of Sandy Hook, curves east through a trumpet interchange with MD 67 (Rohrersville Road), and crosses Israel Creek at Weverton.

The U.S. highway meets MD 17 (Burkittsville Road) at a diamond interchange near Rosemont and crosses Little Catoctin Creek.

[3][12] US 340 and US 15 cross over Ballenger Creek before reaching a diamond interchange with Jefferson Technology Parkway, which is unsigned MD 872G.

[45] However, in December 1940, construction was delayed and plans needed to be modified to eliminate a sharp turn at the Virginia landing of the bridge.

[46] Despite a late request from the Virginia State Highway Department to move the Potomac River crossing upstream in June 1941, the concrete substructure of the Sandy Hook bridge was started in autumn 1941.

[47][52] The Maryland State Roads Commission advertised for bids for the Sandy Hook bridge's superstructure in December 1945.

[22][55] Although the residents of Harpers Ferry lobbied for an on-site replacement of the bridge over the Shenandoah River at Harpers Ferry so US 340 would continue to pass directly through the historic town, the West Virginia State Road Commission completed a new roadway and a new Shenandoah River crossing along US 340's present alignment in 1949.