Needing a win to stay in touch with teams on the lower rungs of the top eight, the Pies were dealt an early blow when star forward Jamie Elliott withdrew due to hamstring soreness and was replaced by Clinton Young.
Skipper Scott Pendlebury then suffered a quad injury in the warm-up and was forced out of the game.
Pendlebury was replaced by Tony Armstrong, who had played a full game for Collingwood's VFL team at Geelong during the afternoon.
The Magpies' night went from bad to disastrous when key position player Ben Reid suffered a hamstring injury in the opening minutes and had to be immediately subbed out.
That meant Armstrong, who started as Collingwood's sub, had to play eight quarters of footy for the day.
If all that wasn't enough to have coach Nathan Buckley tearing his hair out, key forward Travis Cloke went down with an ankle injury during the second quarter and took no further part in the game.
And to top off a horror night, Dayne Beams hobbled from the field early in the third quarter with a knee injury after teammate Ben Kennedy accidentally fell across his leg.
That left Buckley's team with just one player on the bench for the final 50 minutes.
"I have been in the caper 20 years now as a player and coach and I can’t remember a night like it," Buckley said.
"And what is more, I thought we came up against an opposition that were clearly up and about."
The Lions, who six days earlier had lost to Adelaide at the Gabba by 105 points, made the most of the Magpies' bad luck and charged to an 18.15 (123) to 8.8 (56) victory.
They did the majority of the damage in the second and third quarters, when they kicked nine goals to two.
Having been 59 points up at the last change, by which time most of the Collingwood fans in the crowd of almost 33,000 had gone home, they coasted to their first win over the Pies since 2010.
The stats sheet told much of the tale. The Lions finished with 430 disposals to 318 and 59 inside-50s to 43.
"We...played our best football probably for the year, so that was pleasing," victorious coach Justin Leppitsch said.
"I said to the players, 'Nothing's as good as it seems, nothing's as bad as it seems.'
"We're not as bad a team as we were last week, but also understanding tonight that we (played) a very depleted side that had their issues as well.
"We were able to take advantage of that, but we have to keep that in check as well."
Speedy midfielder Dayne Zorko was among the many outstanding players on the winning team. He gathered 23 disposals in the first half and finished with 36 and two goals.
Tom Rockliff, who picked up 43 touches in his 100th game, and Pearce Hanley were also prominent in the middle of the ground.
They received some great service from mobile ruckman Stefan Martin, who ran Brodie Grundy and Jarrod Witts off their feet.
In his second game, key forward Jonathan Freeman led the way in attack with a game-high four goals, while experienced big man Daniel Merrett slotted three.
But Merrett was taken from the ground on a stretcher late in the last quarter after suffering an ankle injury when he fell awkwardly in the goalsquare.
Collingwood's best players were Steele Sidebottom, Brent Macaffer, Dane Swan, who was back after three weeks on the sidelines with a foot injury, and Young.
Small forward Tim Broomhead showed some spark early on, kicking three goals in the first half.
Armstrong, who played across half-back and had to man up on pacy youngsters like James Aish and Jack Crisp, racked up 17 touches in a commendable performance.
The Magpies, who lost to West Coast by 10 goals last weekend, now have a 10-10 win-loss record.
They will need to win their last two home and away matches, against Greater Western Sydney (Spotless Stadium) and Hawthorn (MCG), to have any hope of making the finals.
The Lions remain 15th on the ladder, but they have improved their 2014 record to 7-13.
They host Fremantle at the Gabba next Sunday.
Collingwood 4.3 5.3 6.6 8.8 (56)
Brisbane 6.1 10.7 15.11 18.15 (123)
Goals - Collingwood: Broomhead 3, Goldsack, Cloke, Swan, Fasolo, Young
Brisbane: Freeman 4, Merrett 3, Green 2, Zorko 2, McStay, Beams, Gardiner, Adcock, Hanley, Bewick, Crisp
Best - Collingwood: Sidebottom, Swan, Macaffer, Young
Brisbane: Zorko, Rockliff, Hanley, Martin, Freeman, Adcock
Injuries - Collingwood: Elliott (hamstring) replaced in selected side by Young, Pendlebury (quad) replaced in selected side by Armstrong, Reid (hamstring), Beams (knee), Cloke (ankle)
Brisbane: Gardiner (ankle), Merett (knee)
Substitutes - Collingwood: Ben Reid, replaced by Tony Armstrong in the first quarter
Brisbane: Darcy Gardiner, replaced by Marco Paparone in the fourth quarter
Reports: Nil
Umpires: Leppard, Armstrong, Mollison
Official crowd: 32,926 at the MCG.
