Mthembu, who was second in the last ‘down’ run two years ago, 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 stormed through to grab third place as local athletes swept the podium.
Greenwood, meanwhile, closed down long-time Russian leaders Elena and Olesya Nurgalieva to win the women’s race in 6:18:15.
Elena Nurgalieva finished second in 6:23:18, less than two minutes ahead of her twin sister.
Click here for the full Comrades Marathon 2014 results