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.
Mphuthi used the opportunity to surge past, with a group of six men, including former winners Stephen Muzhingi and Ludwick Mamabolo, chasing him into Pinetown.
He was well clear of the rest of the field with 21km left in the gruelling ultra-marathon.
Defending champion Claude Moshiywa pulled out the race in the first half after struggling with a groin injury.