Lions captain Burger Odendaal inspired the South African side to a bonus-point win against Ospreys at Ellis Park.
Odendaal twice broke clear in the first half to set up tries, first for Rabz Maxwane and then Morne van den Berg.
Reinhard Nothnagel scored a third try to make it 21-3, although Rhys Webb and Michael Collins crossed to keep Ospreys in the contest up to the hour mark.
But Van den Berg, Manuel Rass, Edwill van der Merwe and Andre Warner all scored late on to secure Lions' win.
Both sides started the contest with high intensity at the break down, each forcing early penalties and turnovers.
Nicky Smith was penalised at the scrum after nine minutes gave but Jordan Hendrikse missed a relatively easy kick at goal.
Lions made amends a minute later though, as captain Odendaal forced missed tackles from Webb and Keiran Williams before offloading to Van den Berg.
He in turn passed wide to Maxwane who raced clear to score the game's first try, with Hendrikse making no mistake with the conversion.
The game continued at a blistering pace, Ospreys picking the ball up on halfway after a Lions knock-on and moving it quickly to Luke Morgan on the left, but he lost possession in the subsequent breakdown.
The Welsh region continued to dominate possession and territory, but struggled to break down the Lions defence, though Josh Thomas did kick Ospreys onto the scoreboard after 30 minutes.
Lions hit back three minutes before half-time, with Odendaal the creator once again.
The centre opened up the Ospreys defence for the second time in the match, and his simple offload to Van den Berg saw the scrum-half run in Lions' second try to make it 14-3.
The South African side started the second half as they finished the first, Hendrikse and Maxwane combining on the right to work themselves deep into Ospreys territory.
The Lions forwards then stepped in to finish the job, Nothnagel crossing over to score the third try of the contest.
Ospreys found a much-needed response, Webb with the quick show-and-go dummy pass to beat the Lions defence and squeeze over from four metres out.
Lions secured the bonus point after 54 minutes, Odendaal and Van der Merwe making hard yards before Wandisile Simelane found a gap to break clear and feed Van den Berg.
Lions replacement Rass gifted Ospreys a second try, as his loose pass was intercepted by the grateful Collins and he ran in unopposed to bring the Welsh region back within two scores.
But Rass' next key contribution was at the right end, the centre collecting the ball from a held-up Simelane on the tryline to dab down a fifth.
As Ospreys legs tired, Lions took full advantage in the wide areas, Van der Merwe beating everyone for pace to score a sixth try before replacement scrum-half Warner took the South African's points total above 40.
Victory is a third in a row for the Lions in the URC, as the South African regions remain unbeaten on home soil against northern hemisphere teams.
Ospreys remain in South Africa for their next match, against DHL Stormers on 2 April.
Lions: Quan Horn; Rabz Maxwane, Wandisile Simelane, Burger Odendaal (capt), Edwill van der Merwe; Jordan Hendrikse, Morne van den Berg; Sti Sithole, Jaco Visagie, Ruan Dreyer, Ruben Schoeman, Reinhard Nothnagel, Vincent Tshituka, Emmanuel Tshituka.
Replacements: PJ Botha, JP Smith, Asenathi Ntlabakanye, Ruan Venter, Sibusiso Sangweni, Andre Warner, Manuel Rass, Tiaan Swanepoel
Ospreys: Dan Evans; Keelan Giles, Michael Collins, Keiran Williams, Luke Morgan; Josh Thomas, Rhys Webb (capt); Nicky Smith, Sam Parry, Tom Botha, Rhys Davies, Bradley Davies, Dan Lydiate, Morgan Morris, Ethan Roots.
Replacements: Scott Baldwin, Rhodri Jones, Rhys Henry, Will Griffiths, Harri Deaves, Reuben Morgan-Williams, Tiaan Thomas Wheeler, Cai Evans.
Referee: Ben Blain (SRU)
Assistants: Morne Ferreira & Stephen Geldenhuys (SARU)
TMO: Marius van der Westhuizen (SARU)