McDonald brought the energy with a career-best six-goal haul at the SCG to lift the Swans to a 21.15 (141) to 13.10 (88) triumph after captain Callum Mills went down with a knee injury in the opening quarter on Saturday.
Charlie Curnow and Tom Papley also kicked five goals each in a near-complete Swans performance against the reigning back-to-back premiers in front of 37,261 fans.
Bracing for scans to confirm the dreaded ACL tear for Mills, Sydney will host either Fremantle or Geelong in a preliminary final in their improbable premiership push.
The Swans are already without vice-captain Isaac Heeney, Chad Warner and Nick Blakey, who are among five players serving club-imposed suspensions.
Brisbane will return to the Gabba and host either the Western Bulldogs or Adelaide in a semi-final, as they continue their pursuit of a third consecutive flag.
McDonald was excellent against star Lions defender Harris Andrews, finding redemption in September against the Lions.
The 23-year-old had been kept to one disposal in the 2024 grand final loss before missing the entire 2025 campaign through injury.
Papley had shaken off a left calf issue - picked up during warm-up - to pull off an equal career-best haul, leading alongside midfielder Errol Gulden (34 disposals) and Hayden McLean (three goals).
Swans midfielder James Rowbottom was also superb in nullifying Lachie Neale (18 disposals).
Oscar Allen had four goals for Brisbane, while Charlie Cameron had one behind from four disposals.
Brisbane co-captain Hugh McCluggage (16 disposals) was still rusty on return from a calf injury, leaving it to veteran defender Dayne Zorko (26) to lead the way for the Lions.
Sydney won every quarter in a near-complete performance, setting the tone by firing off six goals to two in a blistering start.
Curnowpulled off a superb speccy off the back of Lions defender Darcy Gardiner to light the spark and set up McDonald's opening goal.
Swans firestarter Papley shook off a left calf issue - which he had picked up during warm-up - and hit the scoreboard twice in the first quarter to help set up a 26-point lead.
The livewire forward had kicked his second goal after Jaspa Fletcher was pinged for insufficient intent for taking the ball between the goal posts.
Mills then went down after he tried to corral Lions youngster Will Ashcroft near the boundary line.
Brisbane got on the front foot after the first break when Oscar Allen kicked back-to-back majors, but the Lions couldn't wrestle momentum as strong wind and rain came to the SCG.
Sydney built their lead to 30 points, with players struggling to read the ball as gusts reached up to 55km/h.
Conditions settled after the main break, but the Swans refused to give up their centre-clearance dominance as Papley continued to dictate the energy from up front.
Inspired by his teammate, Gulden finally hit the scoreboard in the third quarter to send the SCG crowd rocking to Australian Crawl's 1981 hit "Errol" and break the 100-point ceiling.
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