With the ball, the Renegades impressed to restrict the Sixers to 6-150 from their 20 overs.
But they couldn't replicate that in the second innings with the bat, falling 45 runs short to be dismissed for 105 in the 17th over.
After being asked to field first, the Renegades claimed an immediate breakthrough, with Josh Lalor striking to remove Josh Philippe in the opening over.
Experienced leg-spinner Cameron Boyce returned for his first game since BBL|09 and was influential with the ball.
He claimed 2-15 from his four overs and didn't concede a boundary.
Some good catching was on show throughout the Renegades' innings, with Jake Fraser-McGurk and skipper Nic Maddinson hanging onto sharp chances on the boundary
Kane Richardson also struck twice, with both of his wickets coming in a brilliant final over. He finished with 2-37, taking his season tally to 18 wickets - equal second highest in the competition.
But with the bat, the Renegades couldn't find any momentum.
Fraser-McGurk departed in the opening over and was followed by Aaron Finch in the second, both leg before wicket.
Maddinson also fell before the midway point, as the Renegades hit 3-55 at the midway mark.
Shaun Marsh was the mainstay, with a classy 39 off 35 balls. But he fell in a period where the Renegades lost 5-30, in and around the power surge.
Only two other batters - Sam Harper (15) and Richardson (15*) - reached double figures.
Despite the loss, the Renegades remain in finals contention. They sit in sixth position, just behind the fifth-placed Brisbane Heat.
Next up for the Renegades is a home derby this Thursday night, against the Melbourne Stars at Marvel Stadium.