With the Renegades needing 22 runs from the final over for victory, paceman Ben Dwarshuis (3-36) stepped up for the Sixers only days after the sudden death of his father.
He bowled Tom Rogers with the first ball of the over before conceding a six from all-rounder Will Sutherland, the side's last hope, to keep the game in the balance.
But Sutherland (50) swung and missed the penultimate ball of the game, which was then out of the Renegades' grasp with one ball remaining.
The Renegades finished on 7-167 in reply to the Sixers' 6-175 and have not beaten them in four years.
Melbourne were left to rue meagre contributions from the top order, losing captain Nic Maddinson for six in the first over on his return from injury and they stumbled from there.
Young gun Jake Fraser-McGurk (48) was the only man who seriously threatened for the Renegades among their recognised batters, just missing out on his first BBL half-century.
Smith picked up where he left off last BBL summer, setting the tone for the Sixers with his top score of 61 out of their 6-175 after they lost the toss.
After the Sixers lost 2-2 from Sutherland's bowling, Smith steadied the ship during a 69-partnership for the third wicket with a favourite co-conspirator in Moises Henriques.
Smith brought his seventh BBL half-century with a single off Sutherland, who finished with 2-21.
It took long-time Australian teammate Adam Zampa (2-24) to dismiss Smith in the 17th over and prevent the all-out carnage that had crowds flocking to see him last summer.
Also playing his first match on home soil since their one-day World Cup triumph, Zampa enticed Smith into skying a shot to deep square leg, where he was caught by Jono Wells.
Zampa threatened to turn the game on its head as he bowled English all-rounder Tom Curran for a golden duck with his next delivery, but he missed out on his maiden BBL hat-trick.
Nevertheless, the leg-spinner halted the momentum, something the Sixers only regained in a 17-run final over that featured two sixes from Jordan Silk (26no off 14 balls).
A rare clash for Smith with Test teammate Nathan Lyon was put on ice as the superstar off-spinner missed the game to ready himself for next week's Perth Test.
Smith is hoping to play for the Sixers once more this summer in a clash with the Sydney Thunder on January 12, that falls between the Pakistan and West Indies Test series.
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