Route 159 is a state highway connecting the Hartford and Springfield areas in the U.S. states of Connecticut and Massachusetts. It begins as the northern extension of Main Street in Hartford and proceeds northward along the west bank of the Connecticut River towards Agawam, Massachusetts. The route ends at the junction of Route 147 and Route 75 in Agawam center just south of the West Springfield city line. The route was originally designated as U.S. Route 5A in 1932 and was renumbered to its modern designation in 1968.

Route 159 officially begins at the Hartford-Windsor town line as Windsor Avenue, near an interchange with I-91. The road runs along the west bank of the Connecticut River, crossing Interstate 91 a second time. It goes through the towns of Windsor, Windsor Locks, and Suffield (bypassing Suffield center) before crossing the state line into the city of Agawam. In Agawam, Route 159 signage ends at Route 57, but the official route continues north along Main Street to the intersection of Route 75 and Route 147 in downtown Agawam.

Route 159 in Windsor is also known as the Kasmir Pulaski Memorial Highway.

Modern Route 159 roughly follows the path of the Upper Boston Post Road between Hartford and Springfield. In the 1920s, current Route 159 in Connecticut, with a few minor exceptions, was a primary state road designated as State Highway 110. Around 1930, the continuation in Massachusetts was numbered as State Route 5A, which ran along Main Street but continued north along River Road to the South End Bridge, where it crossed into Springfield to connect with U.S. Route 5. In the 1932 state highway renumbering, the route in both Connecticut and Massachusetts was designated as U.S. Route 5A. However, by 1938, Massachusetts redesignated its portion of the route as State Route 5A, truncating US 5A to the state line. The new State Route 5A was also relocated to follow Main Street into West Springfield, then continuing along River Street, Park Street, and Elm Street, where it ended at US 5. In 1968, Connecticut decommissioned its U.S. Route 5A and the road was redesignated in both states as Route 159. The portion in West Springfield, which was not state-maintained, became an unnumbered road.

Mileposts reset at the state line.