Hughes (50) clattered five sixes before Dan Christian continued to hammer the Sydney Thunder's attack at Showground Stadium, finishing unbeaten on 41.
The Sixers scored 4-168 from a 16-over innings that was interrupted twice because of showers.
The Duckworth-Lewis-Stern method meant the Thunder's target was bumped up to 173 from 16 overs.
Jason Sangha's plucky 47 and Daniel Sams' four sixes gave the hosts hope but the escalating required run-rate proved too much, with the Thunder rolled for 142 in the final over.
Legspinner Lloyd Pope, shouldering a bigger load at the Sixers because of injuries to fellow tweakers Steve O'Keefe (calf) and Ben Manenti (neck), claimed the scalps of Sam Billings and Alex Ross.
Pope's key wickets were among many signs of the Sixers' depth as they made it five wins from six games this season, setting an ideal platform to pursue a third straight title.
Fellow youngster Mickey Edwards also excelled for the men in magenta, having replaced offspinning debutant Todd Murphy at the halfway point of Sixers' innings.
X-factor substitute Edwards ended an entertaining knock of 28 from Sams, while he claimed catches in the deep to dismiss Matt Gilkes, Alex Hales and Nathan McAndrew.
Christian smacked six boundaries in a potent 17-ball cameo, while Hughes was likewise impressive after being promoted to first drop.
The Sixers had hoped to inject Pakistan legspinner Shadab Khan, recruited after English pacemen Tom Curran and Chris Jordan returned home, into their XI.
But Shadab sat in isolation on the sidelines throughout the contest.
"We're not actually sure if we're going to see him (Shadab) tonight yet," Sixers skipper Mosies Henriques said at the toss.
"We're still waiting on one last COVID test to come in.
"So if we get confirmation ... then we'll bring him into the game."
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