Major cities and towns along the length of SR 4 include Sanford, Gorham, Windham, Auburn and Farmington.

SR 4 begins at the New Hampshire state line where NH 4 crosses into South Berwick.

SR 4 passes through the city of Sanford, bypassing the downtown area to the east.

US 202 east joins SR 4 north and the two routes begin a lengthy concurrency.

The road crosses the Saco River into Buxton, and SR 117 immediately splits off to the south.

The three routes are cosigned along Main Street, crossing SR 114 in the center of town.

In Windham, the highway passes through the town center before intersecting with US 302 at a traffic circle.

The highway meets SR 26A, a bypass of Gray Village, then interchanges with Interstate 95 (the Maine Turnpike) at exit 63.

Now paralleling I-95 to its east, the highway continues through New Gloucester, where it meets the northern end of SR 231, and then into the city of Auburn.

SR 4 has an interchange with the Veterans Memorial Bridge Connector freeway and continues due north into the town of Turner.

Both routes junction with SR 145 near the center of town, and continue west through Avon and into Phillips.

SR 4 continues northwest along the Sandy River, passing through a series of unincorporated townships and plantations without any major junctions.

The road continues west until it dead-ends at Haines Landing on Mooselookmeguntic Lake.

All of the New England routes used one- or two-digit numbers that were retained across state lines.

In 1931, the Maine State Highway Commission sought to rectify this problem by conducting an experiment in which it would designate a new low-numbered state highway which ran mostly on existing alignments of the original 1925 three-digit intrastate routes, replacing and/or overlapping the original numbers along those alignments.

The number 4 was chosen because the route was originally intended to be a northward extension of US 4 from Dover, New Hampshire, but the American Association of State Highway and Transportation Officials (AASHTO) never accepted the proposal and US 4 was ultimately routed south and east to its present terminus in Portsmouth.

As first designated in 1931, SR 4 extended from its present terminus at the New Hampshire state line to the Coburn Gove-Woburn Border Crossing, running the entire length of western Maine.

While not directly connected to one another, they are linked by a 4.15-mile (6.68 km) stretch of US 202 and SR 4 between Hollis and Buxton.

The northern segment was partially cosigned SR 11 until 1933, and then overlapped by US 202 when it was designated in 1936.

An eastern bypass of Sanford was constructed in the late 1930s and finished by 1941, at which time it was given the SR 4A designation.

As a result, the entire length of this segment of SR 4A is overlapped by other routes.