East of North Adams, Route 2 ascends via a hairpin turn into the Hoosac Range along what is known as the Mohawk Trail.

Route 2 then enters Franklin County, meeting Interstate 91 at an interchange in Greenfield and briefly runs concurrently with I-91.

After its eastern interchange in Phillipston when US-202 departs to the north, Route 2 becomes a four-lane freeway, though not to Interstate standards at most points.

Route 2 continues east to Middlesex County and enters Boston's outer loop at the interchange with Interstate 495 in Littleton.

It continues into Acton, where Route 2 reduces its speed to 45 miles per hour, and becomes a four-lane expressway with at-grade intersections.

After a signalized at-grade intersection with Bedford Road in Lincoln, the highway becomes a four-lane arterial road.Route 2 enters Lexington and heads to Boston's inner belt, and as it crosses Interstate 95/Route 128, it becomes a six-lane freeway with a speed limit of 55 miles per hour.

[citation needed] The highway enters Cambridge, the highway reduces its speed limit back to 45 miles per hour and becomes a five-lane freeway (three lanes heading east, two lanes heading west), with a strip of residential and transit-oriented development on its eastbound side, including an off-ramp that serves the MBTA Alewife Station, Cambridge Discovery Park and development to the south and west of the station.

It winds through the Boston University campus as Mountfort Street and crosses over both the Massachusetts Turnpike and Commonwealth Avenue before heading due east towards Kenmore Square, while running parallel to U.S. Route 20.

Immediately east of the Boston University campus, it crosses into Kenmore Square, which is also the eastern terminus of U.S. Route 20.

[citation needed] The Leominster to Ayer section opened on July 3, 1953, completing the expressway portion from Westminster to West Concord.

The project was intended to solve the traffic and safety problems that had long occurred at the Crosby's Corner intersection (junction of Route 2 and 2A) in Concord.

The project, which was expected to cost $71.9 million, widened Route 2 from Bedford Rd in Lincoln to 300 feet west of Sandy Pond Rd in Concord.

The Army Corps of Engineers published a notice[6] for this project, because of its impact on wetlands at Crosby's Corner.

The improved intersection would include overpasses for local streets, while Route 2 traffic would continue unimpeded at grade.