Mbuthuma put Pirates ahead in the 4th minute, finishing off Mofokeng’s assist just after Otladisa had hit the post for Gallants.
Patrick Maswanganyi doubled the advantage in the 29th minute, unleashing a precise left-footed strike from outside the box after being set up by Oswin Appollis.
The third goal arrived in the 85th minute, with Mofokeng turning scorer after Nkosikhona Ndaba provided the assist.
READ: Orlando Pirates chase more silverware with eyes on league and Nedbank Cup
Despite late pressure from Jaisen Clifford in the final 15 minutes, Gallants – who remain embroiled in a relegation battle at the foot of the table – could not find a breakthrough.
The result moves Pirates to 38 points from 16 matches, opening a six-point lead at the summit.
Coached by Abdeslam Ouaddou, Pirates appear firmly focused on securing silverware, with club legend Benedict Vilakazi having claimed earlier in the week that they possess the best attack in the country.
Attention now turns to Wednesday’s heavyweight clash against second-placed Mamelodi Sundowns at FNB Stadium. A victory would extend Pirates’ advantage to nine points with 13 matches remaining.