Highway 21 is a long lakeside route through Southwestern Ontario, which serves numerous communities along the eastern shoreline of Lake Huron.

At Southampton, the highway veers away from the Lake Huron shoreline and travels east to Owen Sound.

Near Kettle Point, the route abruptly curves north west and begins to parallel the shore of the lake, providing access to the village of Port Franks and The Pinery Provincial Park prior to entering Grand Bend.

The route curves northeast as it enters Bruce County to align with the surveying grid and proceeds out of Amberley towards Kincardine.

[3] Between Amberley and Tiverton, Highway 21 travels straight-as-an-arrow along what was originally a rural concession road through the hamlets of Reid's Corners, Pine River, Huron Ridge and Slade.

Within Tiverton, which acts as the primary town serving Bruce Nuclear Generating Station, traffic must turn to remain on Highway 21.

As it exits southeast from the town, the highway makes a broad curve to the northeast and continues through the hamlets of Underwood and North Bruce.

Between those two places, the highway is generally straight, except at the boundary between Bruce and Grey Counties as well as the descent of the Niagara Escarpment at Springmount.

Several communities line the inland stretch of highway, including Chippewa Hill, Kelly's Corners, Elsinore, Allenford, Alvanley and Jackson.

When James Miller Williams, a Hamilton businessman, set out one day during a drought to dig a well, he chose a spot downhill from an existing oil seep in the village of Black Creek.

New equipment (namely a Caterpillar Excavator), as well as the expertise of Andy Newman, an engineer who was hired when he demonstrated his abilities with the machinery upon passing a construction site on his drive home.

[18] Beginning in 1960, a small bypass of Highway 21 was constructed on the north side of Goderich,[19] avoiding a nearby hairpin turn.

[20] The 160 m (520 ft) curving structure over the Maitland River was completed in mid-1961 at a cost of C$1.39 million and opened ceremoniously on July 17, 1962.