The highway crosses the state border from New Lebanon, New York, into Hancock and runs eastward to Boston, where it ends at Route 2 in Kenmore Square.

It spends the vast majority of its journey paralleling I-90 (Massachusetts Turnpike), which has largely superseded US 20 for through travel.

[2] US 20 is currently the longest numbered highway in the entire country, at an estimated length of 3,365 miles (5,415 km) between Boston and Newport, Oregon.

Becoming the Jacob's Ladder Scenic Byway for the next 30 miles (48 km), US 20 returns to its eastward direction at this point and closely parallels the Mass Pike, having three non-interchange junctions with it before entering the town of Becket and meeting Route 8.

Route 8 northbound forms a concurrency with US 20 to directly serve the town, while the Mass Pike passes south of Becket.

In Russell, US 20 serves as the eastern terminus of Route 23, passes under the Mass Pike, and continues into Westfield to finish off the scenic byway.

US 20, as Boston Road, serves as the southern terminus of Route 21 and proceeds east into the town of Wilbraham, where it continues to parallel the Mass Pike.

Leaving Worcester, US 20 enters the city of Shrewsbury, having another non-highway interchange with Route 140 south of downtown.

Heading almost due north at this point, US 20 crosses into Northborough and turns back eastward, serving as the western terminus of Route 135 in the town center.

The entire length of US 20 in Weston is designated as the Boston Post Road Historic District, since it retains much of its rural 18th-century character.

US 20 briefly continues as Leo F. Birmingham Parkway upon crossing into the Boston neighborhood of Brighton, immediately intersecting the western end of Soldiers Field Road Extension.

[5] US 20 meets Route 2 at the southern end of the Boston University Bridge, crossing over the Mass Pike for the final time without an interchange.

The western terminus is at the junction of US 20 and I-91 in downtown Springfield east of where US 20 crosses the Connecticut River on the North End Bridge.