The Strikers, with Ollie Pope top-scoring on 57 from 39 balls, posted 5-182 at Adelaide Oval in Thursday night's fixture.
Smith then blasted four sixes in his 52 from 31 balls and the Sixers survived a mid-innings wobble to reach 7-183 from 19.5 overs.
Another 50 for Steve Smith!— KFC Big Bash League (@BBL) What a player he is. #BBL14 pic.twitter.com/yq5ajKvTUHJanuary 15, 2025
"It got pretty tight there but we bat pretty deep," Smith told Fox Sports.
"We held our nerve at the end there and got a few away so it was a good win."
The Sixers (13 points) took top spot from the Hobart Hurricanes (13 points) on net run rate but the Hurricanes have two games remaining while Smith's team have just one left.
Adelaide (six points, sixth spot) are all but certain to miss the finals. With one game left, they're two points shy of the fourth-placed Melbourne Stars.
Test great Smith's knock came four days after he cracked 121 from 64 balls against the Perth Scorchers.
He pulled Brendan Doggett for six from his third ball and cleared the boundary three more times to reach 44 from just 20 balls.
Smith registered his half-century from 27 balls but the game turned when Adelaide's Jamie Overton (2-35) took the ball.
The Englishman had Smith caught at backward point and, four balls later, trapped Jordan Silk (three) lbw to finish his over.
Legspinner Lloyd Pope (2-33) outed Moises Henriques on the next ball: the Sydney skipper was adjudged lbw despite getting a thick inside edge onto his pads - the visitors had burnt their sole review when challenging Silk's dismissal.
The visitors had lost 3-4 in a five-ball span but Ben Dwarshuis (30 from 23 balls) and Lachlan Shaw (32 from 21) rallied with a 55-run partnership.
The Sixers needed 23 from the last 12 balls; then 10 runs from Henry Thornton's last over and Hayden Kerr (18 from nine deliveries) and Sean Abbott (seven from five) secured victory.
Earlier, Adelaide slipped to 3-35 before Englishman Pope and Alex Ross (48 from 37) produced a 97-run partnership from 70 balls and Pope's countryman Overton finished with a flourish, smacking an unbeaten 32 from 14 balls.
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