It begins at the Hartford–Windsor town line and proceeds northward along the west bank of the Connecticut River towards Agawam, Massachusetts.

It then crosses the Massachusetts state line into Agawam,[1] where it passes by Six Flags New England before entering the center of town.

[1] Modern Route 159 roughly follows the path of the Upper Boston Post Road between Hartford and Springfield.

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 US 5.

In the 1932 state highway renumbering, the route in both Connecticut and Massachusetts was designated as US 5A.