City star Rhianna Pollicina scored two goals and assisted another while recruit Kathryn Harvey also grabbed a brace as City ultimately ran away with the game at Casey Fields.
Elsewhere, reigning Julie Dolan Medallist Sophie Harding opened her account as Western Sydney let a 2-0 lead slip in a 2-2 draw with Newcastle.
City, last year's premiers and grand finalists, are widely expected to be in contention for trophies again, despite coach Dario Vidosic leaving for the top job at English Women's Super League club Brighton and Hove Albion.
But in their first league game under Michael Matricciani, City were in danger of being on the wrong end of the upset of the round.
WOW!! WHAT A WAY TO START A SEASON 🚀🔥— Ninja A-League (@aleaguewomen) Kelli Brown scores from MILES OUT seven minutes into @PerthGloryFC 's Ninja A-League opener.Watch #MCYvPER live now on 10Play & Paramount+. pic.twitter.com/qZHMJ41igINovember 3, 2024
Perth took the lead when Kelli Brown spotted City goalkeeper Malena Mieres off her line and chipped her from long range.
Brown almost added another in similarly audacious fashion just before half-time - but that shot bounced to safety.
Miku Sunaga doubled Perth's advantage in the 51st minute when her floating chip over Mieres hung in the Casey Fields breeze then dipped into the goal.
City hit back two minutes later when Miranda Templeman parried a fierce Leticia McKenna strike into the path of Pollicina, who pounced from close range, and Harvey toe-poked the equaliser at the front post in the 63rd minute.
Six minutes later, Pollicina put City in front when she turned former teammate Naomi Chinnama inside-out then unleashed a wonderful, curling strike from the edge of the box.
From 2-0 down to 3-2 up in 15 MINUTES 🤯� What a comeback from — Ninja A-League (@aleaguewomen) @MelbourneCity!And how about the finish on the go-ahead goal by Rhianna Pollicina. Superb.Watch #MCYvPER live now on Paramount+. pic.twitter.com/yJhbj4pRx8November 3, 2024
Harvey prodded home her second goal in the 73rd minute, and in the 95th Laura Hughes turned home a Pollicina cross.
At Cessnock Sportsground, Western Sydney took the lead after just four minutes when Newcastle goalkeeper Danielle Krzyzaniak dawdled on the ball and Harding pinched it from her to score.
Harding then slipped through Sienna Saveska to double the Wanderers' lead in the 27th minute.
Newcastle hit back through Deven Jackson just before half-time, before Lara Gooch slipped through Lauren Allan for a 61st-minute equaliser.
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