Route 49 begins at US 20 (Charlton Road) in the town of Sturbridge.

The route heads north as a two-lane expressway with a speed limit of 55 miles per hour (89 km/h).

Route 49 crosses over Interstate 90 (Massachusetts Turnpike) with no interchange as it clips the northwest corner of the town of Charlton.

The highway parallels Podunk Road for most of its course as it passes to the east of Wells State Park and enters the town of East Brookfield.

Route 49 enters the town of Spencer, crosses over CSX's Boston Subdivision rail line, and crosses over the Sevenmile River before it reaches its northern terminus at Route 9 (Main Street).