Chuba Akpom scored the only goal of the game in the 52nd minute as Town were denied an equaliser from the spot later in the half after James Collins doubled-kicked his penalty effort.
Having controlled possession and had more shots on target, defeat was harsh for Nathan Jones’ side, who dropped down to 13th in the table.
The manager opted to make one change for this evening’s match against Boro, bringing Rhys Norrington-Davies back into the starting line-up ahead of George Moncur.
The Hatters – who are now without a goal in the last four away matches – had a fantastic early chance to take the lead against a Middlesbrough side who have lost just once at home in the league this season.
Kiernan Dewsbury-Hall delivered a dangerous corner to the far post, Dan Potts headed the ball back across towards Sonny Bradley, who under pressure, could only flick wide from close range.
Middlesbrough had just a single shot on goal in the first period but score seven minutes into the second half through Akpom.
Marcus Tavernier broke through the middle of the park and laid the ball wide to Marvin Johnson, who crossed low and the striker was able to steer his effort past James Shea.
Jones made a double change shortly after the hour mark with both Ryan Tunnicliffe and Luke Berry introduced and drama ensued not long after.
Glen Rea produced a superb turn and quick shot from distance that Marcus Bettinelli spilled into the path of James Collins, who fired towards goal but was thwarted by the arm of Sam Morsy.
Referee Andy Davies promptly pointed to the spot and awarded Morsy a red card, but the action didn’t end there.
Collins put the penalty away, though the referee consulted his assistant amid complaints from the home side that the Town striker touched the ball twice when taking.
After communication between the two, the goal was disallowed and play resumed with a Middlesbrough free-kick.
Town commanded proceedings against the ten-men of Boro and almost snatched an equaliser right at the death, but Berry was denied by Bettinelli who got down well to save his header on a night it just wasn't to be for Luton Town.
Middlesbrough: Bettinelli; Dijksteel, Fry, McNair, Bola; Morsy, Saville, Tavernier, Johnson (Spence 78), Watmore (Wing 70); Akpom (Assombalonga 78)
Subs not used: Stojanovic, Coulson, Jones, Folarin, Roberts.
Goals: Akpom (52)
Yellows: Assombalonga
Red: Morsy
Town: Shea, Pearson, Lockyer, Bradley (C), Potts; Rea (Clark 87), Mpanzu (Hylton 87), Dewsbury-Hall (Tunnicliffe 62); Cornick (Moncur 76), Norrington-Davies (Berry 62); Collins.
Subs not used: Isted, Cranie, Nombe, Morrell.
Yellows: Rea
Referee: Andy Davies