Rebranded as Narrm for the women's Indigenous Round, the Demons kicked the opening three goals in a scintillating start.
But Ally Anderson (21 disposals) and Jesse Wardlaw (two goals) helped the Lions fight back to post a 6.6 (42) to 4.3 (27) victory on Sunday at Casey Fields in Melbourne.
The result put Brisbane back on top of the ladder as one of just two unbeaten teams after four rounds, along with the second-placed Western Bulldogs.
It was Melbourne's first loss of the season after an impressive start.
The Demons won the previous meeting between the sides - a thriller in last season's preliminary final - and kicked the first three goals inside eight minutes on Sunday to earn a 19-0 head-start.
Brisbane responded and made it a slugfest in wet conditions as Wardlaw twice pounced in goal-mouth scrambles to poke home the Lions' first two goals.
It trimmed the margin to four points by half-time and there was just one kick in it after Zimmorlei Farquharson scrubbed through another goal for the Lions just before three-quarter time.
Sophie Conway roved a marking contest and ran into an open goal to put Brisbane in front for the first time as they ran away with the result, kicking three unanswered majors in the final term.
Emily Bates (16 disposals, four clearances), Cathy Svarc (11, six), Isabel Dawes (12, six) and Conway (17, two) were all outstanding for the Lions.
Lily Mithen (23 disposals), Karen Paxman (21) and Tyla Hanks (16, one goal) were busy for Melbourne and Kate Hore finished with two goals.
Hanks' goal was the Demons' only six-pointer after half-time as they were overrun.
Melbourne take on Carlton on Friday night in round five while Brisbane will start favourites against Richmond.
That fixture will be played at Punt Road Oval, next door to the MCG, starting in the morning of AFL men's grand final day.
A big crowd is expected to filter through before the Geelong-Sydney men's decider.
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