Moises Henriques (53no) produced a captain's knock to secure his wounded outfit's win at the SCG on Monday night, their first step towards avenging a heartbreaking loss to the Brisbane Heat in last summer's final.
Chasing the Renegades' 7-169, Sixers allrounder Ben Dwarshuis hit the winning runs down the ground for four in the 19th over, as his side finished at 5-172.
After the Sixers sent the visitors in, Hughes aggravated an elbow injury diving in an unsuccessful attempt to catch Tim Seifert (55), who topscored for the Melbourne side.
It was the latest in a series of setbacks for Hughes, who had finally been given the chance to cement his spot after two summers in and out of the team.
Hughes's injury forced the Sixers to pump Jack Edwards (37) up to first drop where he forged the innings' best partnership with Englishman James Vince (40) with a 62-run stand for the second wicket.
Renegades skipper Will Sutherland (2-20) provided strong resistance, bowling Vince then having Joel Davies caught behind.
Just as Henriques and allrounder Kerr appeared to be hitting their stride, the latter tweaked his left hamstring running between wickets and called for medical attention.
After stretching failed to alleviate the issue he retired hurt, with Dwarshuis coming in to bat.
The Renegades will have rued a missed opportunity for a run out when the game was on tilt. Although Henriques had slipped over running between wickets, Tom Rogers' throw from mid-wicket could not connect with the stumps.
A dismissal would have left the Sixers teetering at 6-126 requiring 44 in five overs,.
Instead, Henriques clubbed Rogers for four from the next ball in a sign of things to come.
When he smacked Australian white-ball superstar Adam Zampa for two sixes in the 18th over, the Sixers could smell victory to open their campaign.
Earlier, New Zealand white-ball regular Seifert enjoyed a BBL debut to remember, showcasing his reverse sweepÂ
But after he lost control attempting to belt Dwarshuis into the stands and gave an edge to wicketkeeper Josh Philippe, the Renegades' innings never reignited.
Sean Abbott (2-34) was also important with the ball for Sydney, enticing the dangerous Jake Fraser-McGurk into skying to Dwarshuis from his first delivery.
20°C