Millwall's miserable record against Birmingham City continued as goals from Clayton Donaldson, David Cotterill and Wes Thomas made it 15 games without a win against the Midlands side.
Donaldson (32mins) and Cotterill (40mins) put Lee Clark's men firmly in the driving seat, but a second-half fight-back by The Lions saw Lee Gregory reduce the arrears eight minutes into the second-half. Birmingham withstood some intense Millwall pressure before Thomas put the game beyond reach with a decisive third goal with six minutes left.
Lions boss Ian Holloway had threatened to shake things up following Saturday's lethargic display in the 2-1 defeat at Huddersfield. He was true to his word and made three changes to his starting XI, with Gregory handed his full Championship home debut alongside Mathias Ranegie, recalled up front in a diamond formation that saw Shaun Williams sit in front of the back four, Ed Upson and Jimmy Abdou take care of the left and right side of midfield and Scott McDonald sit at the top of the diamond, just behind the front two.
Right-back Justin Hoyte returned to make his first League start since Boxing Day to complete the trio of changes as The Lions looked to bring a disappointing run of one win in eight games to a halt. Aiden O'Brien was also rewarded for his promising performances for the U21s with a place on the bench.
The Lions started with real purpose and twice tested the visiting defence in the opening two minutes. There were just 34 seconds on the clock when a long ball from Scott Malone was headed on by Ranegie into the path of McDonald who drove narrowly wide from 16 yards. Moments later Hoyte's inviting delivery from the right was met by the head of Ranegie, but his effort sailed over the bar.
Birmingham responded and right-back Paul Caddis did well to weave his way into the penalty area before driving a low cross-shot across the face of goal and out for a throw-in on the opposite flank.
Ranegie was a whisker away from breaking the deadlock for Millwall in the 11th-minute, meeting Malone's delicious delivery with a diving header that flew a fraction wide of the upright. Gregory then did well to intercept the ball just inside the Birmingham half and played in Malone, however the left-back's cross was a tad too close to keeper Darren Randolph and he comfortably collected.
McDonald then stabbed agonisingly wide of the target from close-range from Ranegie's knock-down just past the half-hour mark with the best chance of the game.
That proved to be a costly miss and with a rare attack at the other end, Lee Clark's men stunned The Den faithful with the opening goal that was as simple as it was damaging. Cotterill was allowed time and space to work his way into the danger zone and picked out Donaldson who swept home from close range.
It went from bad to worse for The Lions five minutes before the break when Cotterill's 25-yard free-kick evaded a five-man wall and nestled into the bottom corner beyond the reach of keeper David Forde to make it 2-0.
Birmingham could have added a third just 60 seconds later when Cotterill's rising shot was plucked out of the air by Forde as The Lions looked decidedly rocky.
The home crowd left the team in no doubt as to their feelings when the half-time whistle blew, and it was evident when Birmingham's second goal went in that changes were going to be made.
Facing a second-half mountain to climb, Holloway replaced Hoyte and Upson with Richard Chaplow and O'Brien in a bid to get an early foothold back in the game. That so nearly happened just four minutes after the restart when Chaplow's cross was headed over by Gregory and then O'Brien's acrobatic effort flew over the bar.
However it didn't take much longer for The Lions to reduce the arrears when a super bit of play by O'Brien picked out Gregory, and he finished with aplomb for his first ever Championship goal. The goal finally give the home crowd something to cheer about and renewed belief that the final result was anything but a foregone conclusion.
Roared on by the home fans The Lions piled forward and twice spurned great opportunities to level, first when Gregory met Chaplow's delivery and headed straight into the arms of Randolph and then centre-half Mark Beevers saw his powerful header from Williams' free-kick held by the keeper.
Ranegie's stooping header from Malone's delivery landed on the roof of the net with what proved to be the striker's last contribution of the night on 68 minutes and he limped off to be replaced by Fuller just seconds later.
Millwall continued to prise and probe looking for the leveller and it took a smart save by Randolph to deny Williams, blocking the midfielder's fierce drive at his near post.
Fuller used his power and strength to to shrug off a couple of challenges as he burst into the penalty area, only to blaze horribly over the bar with Randolph alone standing between him and goal glory.
Birmingham did well to absorb the pressure and seemed content to try and hit The Lions on the break, and it was from one such counter-attack on 84 minutes that they grabbed the decisive third, killer goal. Cotterill was again involved, this time receiving the ball on the left and picking out Thomas, who made no mistake with a crisp finish.
It took a splendid fingertip save by Randolph to push Beevers' bullet header over the bar and Williams header clipped the foot of the post as The Lions looked for an instant response, but that was about as good as it got with Birmingham's two-goal cushion never really seriously threatened after that.
Millwall: Forde, Hoyte (Chapow, 46mins), Malone, Dunne Beevers; Williams, Upson (O'Brien, 46mins), Abdou, McDonald, Ranegie (Fuller, 69mins), Gregory. Subs not used: King, Webster, Woolford, Briggs.
Birmingham City: Randolph, Grounds, Robinson, Edgar, Gleeson, Donaldson, Cotterill, Reilly (Packwood, 71mins), Arthur (Thomas, 73mins), Davis, Caddis. Subs not used: Doyle, Duffy, Hall, Lee, Shinnie.
Booking: McDonald (87mins)
Scorer: Gregory (54mins)
Bookings: Gleeson (27mins), Cotterill (49mins), Arthur (57mins)
Scorers: Donaldson (32mins), Cotterill (40mins), Thomas (84mins)Ref: R East
Att: 9,086 (away 603)