Highway 21 runs roughly parallel to the main north–south CN rail line between Calgary and Edmonton between Three Hills and Looma.

North of Three Hills, the CN rail line begins to run parallel to the highway, serving most of the communities along the route.

Highway 21 passes the hamlet of Huxley and the access road to Dry Island Buffalo Jump Provincial Park before entering Red Deer County; the Kneehill / Red Deer county boundary also signifies the transition from the prairie to aspen parkland ecosystem, with increasing foliage.

The roadway narrows for the following 23 kilometres (14 mi) as it heads towards the Red Deer River, which it crosses at the Content Bridge.

The route bypasses Bashaw, concurrent with Highway 53 7 kilometres (4 mi), then continues north past Ferintosh and the hamlets of New Norway and Duhamel, crossing the Battle River at an area locally known as Ross' Flats.

North of the hamlet Looma, it enters Strathcona County and reaches an interchange with Highway 14.

[12] Alberta Transportation has long-term plans to replace the Content Bridge across the Red Deer River with a new crossing north of Delburne.