The Hatters have outscored their opposition 7-2 during their four-game winning streak while the Red Devils look to stop their three-match winless run dating back to August.
Luton manager Nathan Jones will be without Dan Potts through injury while Brendan Galloway and Eunan O'Kane are still missing. Tom Lockyer is expected back after a bout of cramps.
Manchester United boss Ole Gunnar Solskjaer is expected to make several changes after the loss to Crystal Palace on the weekend with Dean Henderson, Eric Bailly and Brandon Williams expected to feature.
Luton Town (4-3-3) Sluga; Cranie, Pearson, Bradley, Norrington-Davies; Berry, Mpanzu, Rea; Cornick, Collins, Lee.
Manchester United (4-3-3) Henderson; Williams, Maguire, Bailly, Wan-Bissaka; Beek, Matic, Fred; Rashford, Martial, Greenwood.
Luton have made the best possible start to the new season, winning all four of their competitive fixtures, defeating Norwich City and Reading to reach the third round of this competition while also claiming victory in each of their first two EFL Championship fixtures against Barnsley and Derby County.
United have only played one match so far, a dispiriting 3-1 loss against Crystal Palace in which former Red Devil Wilfred Zaha scored twice. Solskjaer's men have lost their last three matches dating back to the Europa League semifinals against Sevilla, a 1-0 exhibition defeat to Aston Villa and the loss to Palace.
Ones to watch
James Collins netted a hat-trick in the first round victory over Norwich and scored the only goal in the opening day win over Barnsley. Jordan Clark has scored in the Hatters' last two games.
There weren't many bright spots for United on Saturday with Donny van de Beek scoring the Red Devils' lone goal in the defeat to Crystal Palace at Old Trafford representing their lone highlight.
It's been a long time since these last two teams met, a 1-1 draw in the old Division One in April of 1992 marking the most recent matchup. United have won 28 of the previous 39 matchups and have not lost at Kenilworth Road since March of 1987.
How to watch
The match will be broadcast live on Sky Sports on Tuesday, September 21th, with kick off set for 20:15 BST.