The primary north–south route through the central portion of the Niagara Peninsula, Highway 406 connects Welland, Thorold and downtown St. Catharines to the Queen Elizabeth Way (QEW).

Construction resumed in 1987 to extend Highway 406 further south to Welland, albeit as a super two, where it ended at a signalized intersection at East Main Street and this was completed in 1995.

[8] Within St. Catharines, Highway 406 twists frequently, entering the Twelve Mile Creek valley south of a complicated interchange with Westchester Avenue and Geneva Street and curving west.

[11] It passes beneath the high-level St. Paul Street bridge, crosses the creek and intersects Fourth Avenue.

One of the planned routes was a freeway to link Highway 3 in Port Colborne with the QEW, travelling alongside the Welland Canal.

[12] The future route was designated as Highway 406 despite construction not beginning until 1963;[6][13] the first section, between Geneva Street and St. Davids Road, opened December 7, 1965.

The original design plans for Highway 406 called for this section to follow the creek valley the full distance to the QEW, interchanging with it east of Martindale Road.

[6] Realignments to several streets in St. Catharines were completed in advance of construction on overpasses, ramps and the bridges over Twelve Mile Creek; this work was finished in late 1983.

[19][21] Further work to extend Highway 406 as a Super two south towards East Main Street in Welland began during the fall of 1987, including an eastward extension of Woodlawn Road.

Grading and paving of Highway 406 also took place from Woodlawn Road to the route's southern terminus at East Main Street, which was also a signalized intersection.

The existing signalized junction at Woodlawn Road was repurposed for the southbound off-ramp and on-ramp, as continuous Highway 406 traffic was rerouted upon new overpasses.

By September 2015, all the at-grade intersections had been removed and Highway 406 was a minimum four-lane, controlled-access freeway for its entire length.