Interstate 95 (I-95) is a part of the Interstate Highway System that parallels the East Coast of the United States from Miami, Florida, in the south to Houlton, Maine, in the north. In the US state of Massachusetts, it spans 92 miles (148 km) along a north–south axis. It is the third-longest Interstate Highway in Massachusetts, behind I-90 (the Massachusetts Turnpike) and I-495, while I-95 in full is the longest north–south Interstate and sixth-longest Interstate Highway in the US.

Its southern terminus within the state is located in Attleboro, where I-95 enters from Pawtucket, Rhode Island. It intersects with US Route 1 (US 1) and the northern terminus of I-295 within Attleboro, I-495 in Mansfield, and US 1 in Sharon before arriving at an interchange with I-93, US 1, and Route 128 in Canton. At this interchange, I-95 begins running concurrently with US 1 and Route 128 along a beltway roughly 15 miles (24 km) outside of Boston. While earlier plans called for I-95 to run northeastward through Boston along the Southwest Corridor and a more northerly portion of Route 1 known as the Northeast Expressway, these plans were ultimately cancelled due to fierce community opposition. As such, Boston is one of only two major east coast cities that I-95 bypasses (the other, Washington DC, for the same reason).

While its concurrency with US 1 ends in Dedham, its concurrency with Route 128 continues as it meets with expressways including the Massachusetts Turnpike in Weston, US 20 in Waltham, Route 2 in Lexington, US 3 in Burlington (with which it runs concurrently within the town), and I-93 and US 1 in Reading and Lynnfield, respectively. I-95 and Route 128 split in Peabody, as Route 128 travels northeast toward its northern terminus in Gloucester, I-95 continues north and crosses US 1 in Peabody and Danvers. Within Salisbury, it intersects the northern terminus of I-495 and arrives at its own northern terminus, where I-95 continues into Seabrook, New Hampshire, as the Blue Star Turnpike.

I-95 crosses the state border from Pawtucket, Rhode Island, into Attleboro as a six-lane highway, with the first northbound exits, 2A and 2B, providing access to Route 1A and nearby US 1 near the border. (There is an exit 1, but it is a southbound-only exit connecting to US 1 south into Rhode Island). Exits 4–7 (old exits 3–5) also serve the Attleboro area, with exit 6 (old exit 4) at the northern terminus of I-295.

Exits 12A and 12B (old exits 6A and 6B) in Mansfield provide access to I-495, the "outer circumferential" beltway around Greater Boston. I-495 provides northbound connections to Worcester, the Massachusetts Turnpike, and the western part of the state, and southbound connections to Cape Cod. Mansfield is home to the Xfinity Center, a Live Nation Entertainment-owned amphitheater that hosts numerous concert events, and TPC Boston, a PGA Tour player's club that hosted the Dell Technologies Championship yearly. The two venues are located near I-95's interchanges with Route 140. This exit also provides access to Gillette Stadium and the town of Foxborough from areas to the south.

I-95 continues northward into Sharon, it interchanges with US Route 1 at exit 19 (old exit 9), which provides access to the stadium from the north. It then enters Greater Boston and the towns of Walpole, and Norwood, before entering Canton, where it meets I-93 at its southern terminus, and I-93 continues as exit 26 (old exit 12) to the right of I-95, while I-95 traffic is routed in a single lane to a sharp clockwise curve where it meets US 1 in a wrong-way concurrency.

Upon interchanging with I-93, I-95 loops around to the west, taking over the roadbed from I-93 (now four lanes) and joining US 1 southbound in a wrong-way concurrency. Route 128 begins here as well. The highway enters Westwood next, with US 1 leaving the freeway near the Dedham town line to parallel I-95 back to the south. I-95 and Route 128 makes its way around Greater Boston, passing through Dedham, Needham, and Wellesley, where the freeway has an interchange with Route 9, and the freeway widens to eight lanes. Then, the highway passes through Newton, then enters Weston and has a large interchange with the Massachusetts Turnpike (I-90) that provides connections to nearby Route 30. With the exception of between the I-90 on- and offramps, this portion of I-95 is four lanes in each direction.

I-95 and Route 128 are due west of Boston at this point and begin to turn to the northeast, serving the city of Waltham and the town of Lexington along the way. The freeway has an interchange with Route 2 (Concord Turnpike) at exit 45 (old exit 29). Upon entering the town of Burlington, I-95 and Route 128 have an interchange with US 3, the Northwest Expressway, at exit 50A (old exit 32A). US 3 provides a direct freeway connection with the Lowell–Nashua, New Hampshire, metro area. Access to the Middlesex Turnpike and Burlington retail district is facilitated at this interchange as well. US 3 south briefly joins the freeway in another wrong-way multiplex in order to connect with its old alignment, leaving at exit 51A (old exit 33A). I-95 and Route 128 continue northeast through the city of Woburn and into Reading.