Full-time from Kenilworth Road
The Lions were trailing as the game entered the final 20 minutes with the unlucky Shaun Hutchinson putting through his own net to hand the home side a 55th-minute lead.
But the introduction of Fred Onyedinma inspired Neil Harris' Lions and the sub grabbed a 70th-minute leveller before debutant Smith took centre stage, adding his first goals for the club on 81 and 87 minutes to secure victory.
Smith was one of three players making their senior debuts for Millwall, who were missing a number of first team regulars through injury and international duty. Kyron Farrell and Paul Rooney, who have also featured heavily for the U23s this season, were rewarded for their consistent displays with their first starts too.
The game also saw a welcome return to senior action for experienced right-back Shaun Cummings, who returned to the starting XI for the first time since sustaining a knee injury in February.
Frontman Smith went close early on when he headed a deep Aiden O'Brien cross into keeper Craig King's arms and at the other end former Lion Josh McQuoid powered a header from Jack Senior's cross narrowly off target as the teams traded early scoring chances.
The busy Senior provided the ammunition once again, this time for Isaac Vassell, but the striker's close-range header flew over the bar before Vassell worked his way into a good position, only to fire straight into the arms of grateful Lions keeper Tom King.
A smart bit of defending by Rooney denied Jonathan Smith as Luton continued to press, but it was Millwall who so nearly stole the lead on the half-hour mark when Smith's flick was met by O'Brien, whose volley was pushed over by the fingertips of keeper King.
The start of the second-half saw both teams trade scoring chances; Lions keeper King blocking a shot from Vassell after the striker broke through one-on-one and then David Worrall sending a free header from O'Brien's cross over from eight yards.
It was the home side, however, who broke the deadlock 10 minutes after the break when Stephen O'Donnell slipped the ball through to Mackail-Smith and the latter's low cross was deflected into his own net by the unfortunate Hutchinson.
Lions boss Harris responded by introducing Onyedinma and the sub nearly made a sensational entrance, breaking clear on goal seconds after entering the fray and hitting a rasping drive that King flung himself across goal to keep out.
However the sub was not to be denied, and when Gregg Wylde embarked on a scorching 70th-minute run down the left, the former Plymouth man whipped over an inviting cross that Onyedinma thumped home.
Left-back Joe Martin hit a crisp 25-yarder that was tipped over by the keeper as Millwall began to turn the screw and that pressure finally paid off in the 81st-minute. Calum Butcher did well to work an opening in a central position and when his 16-yard drive was parried by King, there was Smith to react quickest and lash home the loose ball.
The debutant wasted little time - six minutes to be precise - before adding his second of the night. Worrall whipped over an inch perfct freekick from the right and the towering head of Smith did the rest with a bullet header to put the result beyond doubt.
He could even have had a third right at the death, but was inches away from connecting with a corner. A fourth goal would have been harsh on the Hatters, but for Millwall, the real prize is securing a home tie when the draw for the next round of the competition is made on Thursday.
Scorer: Hutchinson (55mins, og)
Booking: Smith (66mins)
Scorers: Onyedinma (70mins), Smith (81, 87mins)
Att: 2,251 (away 370)
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