The Lions looked winners at half-time, leading by 20 points, but superstar Christian Petracca had other ideas, putting Melbourne on his back to carry it to a 14.13 (97) to 11.9 (75) victory.
Clayton Oliver (26) came to life after the main break, as did the forward duo of Kysaiah Pickett and Tom McDonald, who had been starved of opportunities in the first half.
Melbourne had the game under control in the second half, dominating at stoppages, generating run from most parts of the ground and slowing the Lions' ball movement.
Brisbane played an almost flawless first half, but looked to tire badly late in the game.
Max Gawn played rover to give his team an early lead with a superbly snapped left-foot goal, before the Lions flexed their muscles, kicking the next three to take control.
Zac Bailey miraculously soccered one from mid-air to kick one of his four goals, while Eric Hipwood, Joe Daniher and Lincoln McCarthy were all dangerous aerial threats.
The Lions owned the footy with 43 more disposals leading to 14 more inside 50s, and could have led by more if two of Hipwood's long-range set shots didn't thump into the woodwork.
Oscar McInerney also proved dangerous from inside 50 stoppages, once hitting into the path of Charlie Cameron for a goal, and another time tapping to the advantage of Dayne Zorko who found Bailey for a neat finish.
One highlight for Brisbane will be the fact that Brownlow Medallist, Lachie Neale, got through the physical contest unscathed.
After missing five weeks following ankle surgery, all eyes were on Brownlow medallist Lachie Neale in his return. The brilliant Lions midfielder worked his way into the game nicely, finishing with 25 disposals, including nine clearances.
The anticipated James Harmes tag never really eventuated, although the Melbourne stopper lined up alongside Neale at some stoppages. Neale still worked hard in the final term when many of his teammates battled and should be better for the run.
MELBOURNE 2.3 5.4 10.9 14.13 (97)
BRISBANE 4.4 8.6 10.8 11.9 (75)
Melbourne: McDonald 3, Pickett 3, Fritsch 2, Petracca 2, Gawn, Jackson, Neal-Bullen, Sparrow
Brisbane: Bailey 4, Cameron 2, Coleman, Daniher, Hipwood, McCarthy, Zorko
Melbourne: Petracca, Harmes, Oliver, May, Gawn, Neal-Bullen
Brisbane: Zorko, Bailey, Lyons, Andrews, Neale
Melbourne: Baker (unused)
Brisbane: Mathieson (unused)
Crowd: TBC at Giants Stadium