Route 99 begins at the intersection of New Rutherford Avenue and Chelsea Street, over the northbound tunnel of U.S. Route 1 created during the Big Dig. It continues along New Rutherford Avenue, passing onramps to Route 1 and Bunker Hill Community College before entering Sullivan Square, where Route 38 begins next to the MBTA station. It then turns northeastward onto Alford Street, crossing the Malden Bridge over the Mystic River. After passing through a small strip of Boston on the east banks of the river, the route enters Everett and becomes Broadway.
Broadway crosses through Sweetser Circle, the intersection with Route 16 and the Revere Beach Parkway. The route continues northeastward into the city of Malden, where it intersects Route 60. The route continues on through a short (0.25 miles (0.40 km)) corner of Melrose before entering Saugus. Once in Saugus the route terminates at ramps leading back to Route 1.
Sweetser Circle has been the site of numerous major accidents, including a gas tanker rollover early on December 5, 2007 that resulted in 9,400 U.S. gallons (36 kL) spilling, igniting and destroying 21 vehicles and two large multi-family homes.
Prior to the designation as Route 99, the entire route was part of US-1 before the construction of the Northeast Expressway.