Western end (Pittsfield – Worcester)

It begins in the western Massachusetts city of Pittsfield, at U.S. Route 20. After separating from US-20, it has a brief .2 mile concurrency with U.S. Route 7 through the center of that city, then continues east, passing through the towns of Dalton and Windsor, wherein the route reaches its highest point at 2033 ft, in Berkshire County. It continues its winding pass through the small towns of The Berkshires in Berkshire and western Hampshire Counties before passing through the center of Northampton, passing Smith College before its first interstate junction, at Interstate 91. It then crosses the Connecticut River at the Calvin Coolidge Bridge, just downstream from Elwell Island. It goes through the retail area of Hadley before passing the University of Massachusetts Amherst and Amherst College. From Amherst, it winds its way into western Worcester County, south of the Quabbin Reservoir, through small towns until it makes its way into the city of Worcester.

Through Worcester

Once in Worcester, Route 9 becomes a major thoroughfare through the city, as Park Avenue, Highland Street (which passes Major Taylor Boulevard), before passing over Interstate 290 and Belmont Street, where University of Massachusetts Medical School and the former Worcester State Hospital are located. At its intersection with McRae Ct., it becomes a divided highway with raised median.

In the MetroWest region (Worcester – Wellesley)

From Worcester, it crosses Lake Quinsigamond into Shrewsbury. At this point, Route 9 becomes the main retail artery of the MetroWest region. Several plazas and chain stores are located along the route as it makes its way towards Northborough, where it crosses U.S. Route 20; Westborough, where it crosses Interstate 495; and eventually in the Golden Triangle retail area of Framingham and Natick, after crossing the Massachusetts Turnpike. It passes Shopper's World and the Natick Mall, New England's largest mall.

In Greater Boston (Wellesley – Brookline)

Beginning in the Golden Triangle, Route 9 becomes one of the major routes into Boston, serving as a valuable bypass to the Mass Pike and its tolls. It crosses Interstate 95 (also known as Massachusetts Route 128) in Wellesley before crossing the Charles River into Newton and Brookline as Boylston Street. It enters the city of Boston by crossing over Brookline's former namesake, the Muddy River, part of the Emerald Necklace. At this point it briefly becomes Washington Street, then Huntington Avenue, also known as "Avenue of the Arts".

Eastern end in Boston

It loses its raised median briefly between its intersection with S. Huntington Ave. and Brigham Circle. It passes the Longwood Medical and Academic Area, which includes Brigham and Women's Hospital, Harvard Medical School and other hospitals; the Museum of Fine Arts; and several colleges and universities, including Northeastern University. This stretch is also a major site of baseball history; the first game of the 1903 World Series, baseball's first true World Series, was played at the Huntington Avenue Grounds, the original home of the Boston Red Sox. (The site is now part of Northeastern's campus.) The E branch of the MBTA Green Line roughly follows Huntington Avenue underground from Copley Square until it rises above ground at the Northeastern portal.

It then operates in a dedicated median of Huntington Avenue between Northeastern University and the Brigham Circle stop, where trains begin street running in mixed traffic to a terminus at Heath Street. Route 9 continues past Symphony Hall and The First Church of Christ, Scientist, which is the mother church of Christian Science. It then passes Copley Place and the Prudential Center complex, before splitting, the eastbound half onto Stuart Street, the westbound onto Saint James Avenue, past Copley Square; both the eastbound and westbound segments of Route 9 end at Route 28.