The M21 officially starts at the M25 interchange between Phoenix and KwaMashu as Malendela Road.

It heads through KwaMashu in a southwesterly direction, passing through the KwaMashu Central Business District (CBD) and then turning to a south-southwesterly direction to intersect the M5 Dumisani Makhaye Drive (to Mt Edgecombe-via the R102 and New Germany).

After the M5, the M21 proceeds to enter into Newlands West as Inanda Road, bordering the township to the east and winding down the hilly topography in a south-easterly direction until it meets the N2 highway (to KwaDukuza and Port Shepstone) at the Exit 170 interchange.

Shortly after, the M21 intersects with the R102 Chris Hani Road (to Avoca and Durban CBD).

It borders the Durban North suburbs of Umgeni Park and Prospect Hall to the south before ending at the M4 interchange (Exit 3).