The catalysts for Lions' victory were Neil McKenzie (68 not out off 41 balls) and 19-year-old Quinton de Kock (51 not out off 33) as the duo helped the side chase the target of 158 with seven balls to spare at the New Wanderers Stadium.
Mumbai posted 157 for six after being invited to bat and then failed to find an answer for McKenzie and de Kock's joint assault that left them bruised and battered.
For the record, Mumbai had lost to Lions in the second edition of the event two years ago.
It could have been anybody's game till Dhawal Kulkarni and Mumbai skipper Harbhajan Singh were taken to the cleaners in the 16th and 17th over.
While Kulkarni conceded 17 runs, Harbhajan was smashed for 16 as Lions inched towords the target.
Kulkarni's three overs went for 37 while Harbhajan gave away 36 in his four. Pragyan Ojha was knocked for 19 in his two.
Lions lost their first wicket when Ambati Rayudu pulled off a blinder at cover, holding on to Alviro Petersen's full-blooded shot off Lasith Malinga.
Bringing himself on in the seventh over, Harbhajan was on the money straightaway as he got Ghulam Bodi to edge one to first slip where Rohit Sharma completed a good catch.
At 37 for two in the seventh over, the prospect looked gloomy for Lions. However, an unbeaten 121-run partnership for the third wicket between de Kock and McKenzie sealed the match in Lions' favour.
While de Kock was the more dominant of the two initially, the experienced Mckenzie, who got off the mark with a reverse- paddle four off Harbhajan, too played his part before launching into a flurry of boundaries.
The 50-partnership between the two was up in six overs and they continued to torment the Mumbai bowlers till the task was achieved.
Earlier, Mumbai relied on useful contributions from their batsmen to reach a total, which did not prove to be enough.
Mitchell Johnson scored 30 while Rohit Sharma and Dwayne Smith fell in the 20s after getting starts. Dinesh Karthik scored a breezy nine-ball 19 towards the end.
Helping the visiting side to a great extent was the 24 extras conceded by Lions.
Mumbai were off to a brisk start as Smith smashed half a dozen fours to put the South Africans under pressure first up.
Chris Morris erred in line and the easy pickings were treated with disdain by Smith. The bowler, however, had the last laugh when he had the West Indian trapped in front of wicket.
After missing out on the strike initially, Tendulkar steered Sohail Tanvir in front of backward point for his first boundary.
Tendulkar found the fence one more time before left-arm spinner Aaron Phangiso disturbed his stumps after the batsman tried to make room and launch into a heave.
This was the fourth time in recent months that Tendulkar has been bowled. He got out in similar fashions thrice in the Test series against New Zealand in August-September. The bowlers, though, were pacers on those occasions.
Till the time he was there in the middle, Sharma gave Mumbai solidity, playing some opportunistic shots before Dirk Nannes cleaned him up.
Sharma was severe on Zander de Bruyn who was smashed for a six and two fours, the maximum sailing over point region.
The promotion of Johnson, who is returning from a toe injury, ahead of specialists Ambati Rayudu and Karthik, and the powerful Kieron Pollard, seemed to have boomeranged on Mumbai as they lost momentum halfway into the innings.
Though he top-scored for the visitors, Johnson gobbled up a lot of balls, and it was largely due to Karthik's enterprise towards the end that Mumbai reached a respectable total.