One year later, US 220 was realigned north of Williamsport, Pennsylvania, to connect to the New York state line at South Waverly; this supplanted most of what was originally designated U.S. Route 711.

From Rockingham, US 220 travels north through Richmond County to Ellerbe, where US 220 begins to follow a newly constructed four-lane bypass.

The two highways continue in close proximity through Montgomery and Randolph counties, serving the towns of Candor, Biscoe, Star, and Seagrove.

US 220 Alternate rejoins its parent near the North Carolina Zoo, at which point the old path of US 220 continues into Asheboro and Randleman as US 220 Business.

The US 220 freeway, meanwhile, skirts the west side of both cities and proceeds to Level Cross, a small community south of the Guilford County line.

The three routes separate northeast of the city center, with US 220 continuing west on Wendover Avenue along the northern edge of downtown Greensboro.

It eventually exits onto Battleground Avenue, which takes the route north out of Greensboro and into Summerfield and Rockingham County.

[citation needed] The proposed I-73 would generally parallel US 220 between Greensboro, North Carolina, and Roanoke, though funds have not been allocated for the project and some local residents prefer efforts to fix US 220.

Locally, a section in Botetourt County was renamed in 2022 to honor Norvel Lee (1924-1992), a native of Eagle Rock who became a Tuskegee airman, Virginia's first Black Olympic champion, decorated federal civil servant and successful plaintiff in a desegregation lawsuit.

At the top of Knobly Mountain northwest of Ridgeville, US 220 splits from US 50 and resumes a northerly alignment as it descends into the New Creek Valley.

At the northern edge of Keyser, US 220 crosses the North Branch Potomac River via Memorial Bridge, leaving West Virginia and entering Maryland.

4 miles (6 km) north of Cresaptown, US 220 joins with I-68 and US 40, known as the National Freeway west of Cumberland and the Baltimore Pike east of the city.

The three routes head across Wills Creek and through Cumberland to exit 46, US 220 turns north again onto an upgraded roadway opened to traffic on September 18, 2000.

I-99 heads north along US 220, and the resulting overlap duplex continues northeast along the west side of Dunning and Brush mountains.

North of State College, US 322 diverges eastward at the Mount Nittany Interchange while US 220 and I-99 continue northward toward Pleasant Gap.

Past Lock Haven, US 220 runs alongside the west branch of the Susquehanna River, becoming an at-grade road north of Jersey Shore for 6.2 miles until it reaches W Fourth St south of Williamsport.

The Interstate Highway turns to the south, following the Susquehanna River toward Muncy while US 220 exits the expressway onto a two-lane road that first travels east to Hughesville, a borough based around US 220's junction with Pennsylvania Route 405 (PA 405).

A short section of super-two limited-access freeway is used to bypass Towanda, a borough 16 miles (26 km) north of Dushore on the banks of the main Susquehanna River.

Here, US 220 becomes a freeway for the final time at an exit with PA 199, the main north–south highway through the neighboring boroughs of Athens, Sayre, and South Waverly.

The route comes to an end at its interchange with the Southern Tier Expressway, which at this point has briefly crossed into Pennsylvania, within sight of the state line.

At the time, the route followed Keystone Avenue through Sayre to South Waverly, where it turned onto Bradford Street.

The highway turned again after three blocks, proceeding north on Pennsylvania Avenue to the state line and into the adjacent village of Waverly, New York.

In 2017, the American Association of State Highway and Transportation Officials (AASHTO) approved a request by New York and Pennsylvania to delete US 220 north of I-86/NY 17.

[citation needed] US 220 was realigned to follow the new highway, which began southwest of Athens and ended at a junction with Chemung Street less than 0.1 miles (0.16 km) north of the state line.

US 220 was realigned onto US 322 and a limited-access highway running from State College to Bellefonte on May 30, 2003, at which point the previous route via Milesburg was redesignated as US 220 Alternate.

The southern terminus of US 220 in Rockingham was originally at the intersection of East Broad and Hancock streets (US 1 and US 74), where a sign said "US 220 Ends Here".