The section between Orangeville and Primrose was formerly part of Prince of Wales Road, which continues northwards after the highway turns west.

The highway presses north-northwest through farmland and rises gradually over the Niagara Escarpment, a UNESCO World Biosphere Reserve.

It passes between several large quarries and through Caledon Village before entering Orangeville at Highway 9, where it diverges from Hurontario Street.

[7] Highway 10 passes to the east of Orangeville on a bypass, switching between Hurontario Street and Prince of Wales Road alignments to avoid the business district.

[1][7] Historically, Highway 10 follows the 19th-century stagecoach route known as the Toronto–Sydenham Road (the southern half of which later became absorbed into Hurontario Street).

It travelled north from Dundas Street (later Highway 5) in Cooksville through Brampton, Orangeville and Shelburne to Owen Sound.

[9] It was later extended south from Cooksville when the provincial government assumed the remaining stretch to Lakeshore Road (Highway 2) in Port Credit, on the north shore of Lake Ontario, on March 16, 1921.

[27] As Mississauga was established in 1968 from Toronto Township (which included Cooksville),[28] and later Port Credit, and began to rapidly urbanize and as Brampton grew during the same period, portions of Highway 10 were designated as connecting links and transferred to municipal maintenance through the two cities.

On April 1, 1970, a 5.2-kilometre (3.2 mi) segment of the route, from the Port Credit railway underpass to Burnhamthorpe Road, was designated as such.

This was followed on December 10, 1970, with the creation of a 2.0 kilometres (1.2 mi) connecting link between Steeles Avenue to south of Clarence Street near downtown Brampton.

From Shelburne north to Owen Sound, it remains a two-lane highway with several passing lanes in hillier regions.