An all-spin powerplay from the Renegades reaped the rewards; skipper Sophie Molineux removed Shafali Verma for a golden duck, before the off-spin of Harmanpreet had Ashleigh Gardner (7) caught behind and Alyssa Healy (5) caught and bowled.
From 3-12, Sixers captain Ellyse Perry went about the rescue job with Nicole Bolton (38 off 41).
Perry hit just nine runs from the first 25 balls she faced but she accelerated late in the innings, hitting 41 off the next 26 as she finished unbeaten on 50 from 51 balls.
But it was an all-round dominant display from the Renegades' spinners and medium pacers, who covered the major loss of injured leg-spinner Georgia Wareham to restrict the Sixers to 4-118.
Harmanpreet (2-17) led the wicket-taking, while off-spinner Ella Hayward (0-21) was economical in her return to the XI.
In reply, Eve Jones replaced Molineux at the top of the order and the move paid off, with the English left-hander finding the boundary four times and clearing it once on her way to 38 from 30 deliveries.
It took a disastrous mix-up between Jones and opening partner Jemimah Rodrigues to gift the Sixers their first wicket, with the India star run out for 14.
Courtney Webb (23 off 25) joined Jones to steer the Renegades chase and while the England import was undone by the pace and bounce of Stella Campbell in the 10th over, India captain Harmanpreet Kaur picked up where she left off.
A late hiccup which saw Radha Yadav take a sharp return catch to dismiss Webb was not enough to derail the Renegades' chase, as Kaur smacked back-to-back sixes off spinner Ashleigh Gardner to seal victory with 18 balls to spare.
It was not all bad news for the Sixers, who welcomed back Lauren Cheatle for her first match of the season as the left-armer took the new ball, finishing with 0-17 from two overs in her first elite match since March.
Both teams now travel to Perth, where they will meet in a rematch at Lilac Hill on Saturday.
Sydney Sixers WBBL|07 Schedule (All AEDT Start Times)
Sat 30 Oct | v Melbourne Renegades | 1:25pm | Lilac Hill | Foxtel/Kayo/cricket.com.au
Sun 31 Oct | v Perth Scorchers | 4:50pm | Lilac Hill | Foxtel/Kayo/cricket.com.au
Wed 3 Nov | v Hobart Hurricanes | 1:25pm | WACA Ground | Foxtel/Kayo/cricket.com.au
Tues 9 Nov | v Brisbane Heat | 2:35pm | Karen Rolton Oval | Foxtel/Kayo/cricket.com.au
Wed 10 Nov | v Adelaide Strikers | 4:50pm | Karen Rolton Oval | Foxtel/Kayo/cricket.com.au
Sat 13 Nov | v Brisbane Heat | 7:05pm | Great Barrier Reef Arena | Seven/Foxtel/Kayo
Sun 14 Nov | v Sydney Thunder | 1:40pm | Great Barrier Reef Arena | Seven/Foxtel/Kayo
Sat 20 Nov | v Adelaide Strikers | 1:40pm | Adelaide Oval | Seven/Foxtel/Kayo
Sun 21 Nov | v Perth Scorchers | 10:15am | Adelaide Oval | Seven/Foxtel/Kayo