It starts by heading north-east as a dual carriageway named Quagga Road, forming the eastern boundary of the Proclamation Hill suburb and meeting the western termini of the M7 route (which connects to Fountains Valley) and the M2 route (which connects to Arcadia).

The M22 joins the R104 and they are one road eastwards as WF Nkomo Street through Pretoria West up to the junction with the M1 route (Es'kia Mphahlele Drive).

Just after meeting the M18, the M22 becomes one street eastwards (no-longer one-way streets), crosses the Apies River and meets the M5 route (Steve Biko Road) adjacent to the University of Pretoria Basic Medical Sciences Building in Prinshof.

The M22 continues eastwards through the suburb of Rietondale as Soutpansberg Road, meeting the southern terminus of the M29 route (Parker Street).

After Rietondale, the M22 meets the M7 route (Stead Avenue; Gordon Road) for the second time in the suburb of Queenswood.