The Nedbank runner, winner of three previous gold medals in one of the world’s most famous ultra marathons, crossed the finish line in five hours, 28 minutes, 34 seconds (5:28:34).
Zimbabwean Marko Mambo had taken over from long-time leader Gert Thys, who faded and started to walk with around 30km remaining in the 89km race.
Mambo, however, was hit by severe leg cramps at the top of Fields Hill and collapsed on the floor, writhing in pain.
Mthembu’s countryman, Joseph Mphuthi, used the opportunity to surge past and took control as the elite men entered the crucial final stage of the race.
Behind him, Rufus Photo pushed hard down Fields Hill in an attempt to close the gap while a group of six men, including former winners Stephen Muzhingi and Ludwick Mamabolo, chased him into Pinetown.
However, Mphuthi and Photo both faded as Mthembu broke away approaching the steep climb down Cowie’s Hill with less than 20km left.
Putting down the hammer, he steadily increased the gap to win by nearly five minutes from defending ‘down’ run champion Ludwick Mamabolo.
Gift Kelehe, brother of 2001 winner Andrew, came third in a time of 5:34.39 with Muzhingi (5:35.18) of Zimbabwe fourth, followed by countryman Photo (5:35.30) fifth.