The Johannesburg-based side, beaten finalists in the competition in the previous two seasons, scored tries through props Ruan Dreyer and Jacques Van Rooyen, lock Marvin Orie and hooker Malcolm Marx as their pack dominated in the set-pieces and driving maul.
They also managed a penalty try, while wing Sylvian Mahuza and scrumhalf Ross Cronje crossed over in what was a dominant second half performance.
The Bulls, who played for almost 10 minutes with 13 players following yellow cards in quick succession for prop Conraad Van Vuuren and loose-forward Nick de Jager, scored their tries through wings John-Ben Kotze and Travis Ismaiel, centre Handre Pollard and prop Lizo Gqoboka.
The home side were in the game at the 50-minute mark with the scores level at 21-21, but boosted by their numerical advantage, the Lions pulled away in the final half-hour to record a third successive victory this season and inflict a first defeat on the Bulls.
"Credit to the Bulls, they played extremely well. We had to fight. Our mauling set a good platform. One or two soft moments let them (the Bulls) in though," Lions captain Warren Whiteley said at the post-match presentation.
The Bulls were forced into a change before the game when captain Burger Odendaal was withdrawn because of a rib injury, prompting a move for Springbok flyhalf Pollard to inside centre and Marnitz Boshoff taking over in the number 10 jersey.
The Lions had built a 21-9 advantage just past the half-hour mark, but after Kotze dotted down in the corner and Pollard capitalised on an error from Cronje, the Bulls had clawed their way back to level the scores just after halftime.
Marx barged over to regain the lead again for the Lions, and then followed the two yellow cards in a minute for the Bulls for repeated infringements and that opened the door for the visitors to seize control of the game.
"We fought well, but the yellow cards were too much to recover from," Pollard said. "All over we need to improve. We are building something, but it is not going to get there overnight."