The Highway 403 designation was first applied in 1963 to a short stub of freeway branching off the QEW at Burlington, and the entire route was completed on August 15, 1997, when the section from Brantford to the then-still independent Town of Ancaster was opened to traffic.

[6] East of Ancaster, the freeway passes through a short greenbelt, with Hamilton Golf and Country Club lying to the north.

[8] As the freeway continues north, it crosses an isthmus between Hamilton Harbour and Cootes Paradise alongside several roads which it has served to replace.

The freeway continues straight for several kilometres, passing by the Burlington Transmission Station, until it approaches the Freeman Interchange where the opposing carriageways split apart to accommodate the left-hand exit/entry of the flyover ramps marking the western terminus of Highway 407, then it merges with Queen Elizabeth Way.

[4] Highway 403 travels concurrently with the QEW for 22.6 km (14.0 mi) between the Freeman Interchange and Oakville, a straight section surrounded almost entirely by commercial units and warehouses.

[4] A portion of the Mississauga Transitway express bus service utilizes the freeway's right shoulders between Erin Mills Parkway and Mavis Road.

[5] After a split with Eastgate Parkway where exiting drivers can access Eglinton Avenue or Cawthra Road at a signalized intersection, Highway 403 abruptly curves to the north.

[5] The portion of the highway between Hurontario Street and Eglinton Avenue is the busiest along the route, with approximately 180,000 vehicles travelling it on an average day in 2016.

[13] Planning for the route was underway by 1958, as a portion of QEW was realigned from its original alignment of Middle Road to the Freeman Diversion which also included three-legged junction for the future Highway 403.

[25] An existing portion of Highway 2 served as the connector between the Woodstock-Brantford and Ancaster-Hamilton segments, until the last phase between Ancaster and Brantford finally opened in 1997.

John Graves Simcoe was tasked with defending Upper Canada from the United States following the American Revolution and with opening the virgin territory to settlement.

[28] The paving of the divided four-lane Middle Road, with gentle curves, a grass median, and grade-separated interchanges, would set the stage for the freeway concept.

A portion east of Woodstock was rebuilt in this fashion, but World War II would put an end to McQuesten's ambitions, at least temporarily.

[12] The end of the Korean War in 1953 heralded the resumption of freeway construction in Ontario; the advances in machinery more than made up for lost time.

This tedious project, which required extensive rock blasting, was soon accompanied by construction from Mohawk Road to Highway 2 near Ancaster.

[35] However, local residents complained the new section lacked any barriers preventing children from wandering onto the highway, postponing the ceremony until August 27 as temporary snow fencing was erected.

[36] Over the following week, Minister of Highways George Gomme met with residents and reached a compromise whereby a 24-hour patrol was established to watch for children until a proper fence could be constructed.

As Toronto's anti-expressway movement gained momentum, provincial plans shifted the Hamilton Expressway to the west near Etobicoke Creek.

[41][42] The right-of-way originally intended for Highway 403 between Cawthra Road and Etobicoke Creek was eventually used for a controlled-access arterial extension called Eastgate Parkway, which was planned beginning in 1982.

[19] Portions of the freeway through Mississauga were built alongside established communities, leading to angry homeowners' associations pressuring the province for noise mitigation measures and compensation.

[19][51] In the late 1980s and early 1990s, the Mississauga section of Highway 403 was the site of more than two dozen fatal accidents over a five-year period, one of the highest rates in North America at the time, despite being up to modern road standards.

In this section, Highway 403 features a downward slope as motorists head eastbound towards the Mavis Road interchange; drivers complain of having to slam on the brakes when traffic comes to a standstill, leading to rear-end collisions.

[17] Transportation minister Ed Fulton ceremoniously opened the new freeway connection on September 26, 1988, completing the Woodstock to Brantford link.

[59] On March 24, 1987, Chris Ward, MPP for Wentworth North announced that construction of the missing link between Brantford and Ancaster would begin in 1989.

To resolve this, the renamed Ministry of Transportation began planning for the missing link of Highway 403 between Burlington and Mississauga that would run parallel to the QEW;[63] this right-of-way would be sold to the 407 ETR consortium in 1995 and built as part of that route.

[64] Work began in August 1991 to reconfigure the directional T interchange to modern standards which included realigning the QEW carriageways as mainline traffic, and adding a fourth leg for the future Burlington-Mississauga link, although this necessitated replacing the directional ramp with a lower-capacity loop ramp for the movement from Toronto-bound QEW to the Brantford-bound Highway 403 (as some traffic was expected to be diverted away from the Burlington Skyway to the under-construction Lincoln M. Alexander Parkway and planned Red Creek Expressway).

[65] The completed ramps (the first to be built were cast-in-place post-tensioned bridges to cross Highway 403 westbound, followed in 2000 by precast girder bridges to pass over the North Service Road[66][67]) connecting to the future Burlington-Mississauga freeway sat unused until that segment finally opened on July 30, 2001, as part of Highway 407 ETR.

[75][76] The HOV lanes and the dividing Ontario Tall Wall concrete barrier were constructed using the existing right-of-way provided by the grass median.

[77][78] Metrolinx began construction of the Mississauga Transitway West between Winston Churchill Boulevard and Erin Mills Parkway[79] in October 2013, including realignment of hydro towers and new bus-only lanes crossing the existing ramps on the north side of Highway 403's interchange with Winston Churchill Boulevard, which was completed on December 31, 2016.

The existing bridges carrying QEW traffic across Ford Drive and the eastbound ramp to Highway 403 were demolished and replaced by new wider structures which can accommodate future HOV lanes and high-mast lighting.