Jamie Vardy opened the scoring for the Foxes before a Juan Mata double helped United take the lead. Poor defending then saw Harry Maguire score late on as the Red Devils eventually dropped two crucial points.
Currently 13 points behind table-toppers Manchester City, United cannot afford to drop anymore points as they host high-fliers Burnley next on Tuesday.
Despite their recent 3-0 home loss to Tottenham, Sean Dyche's side are exceeding expectations this season and are currently sitting comfortable in seventh place with 32 points from 19 games.
According to the Manchester United website, stand-in captain and right-back Valencia, who has missed the last two games with a hamstring injury suffered against West Bromwich Albion, is a doubt for the Burnley clash.
Valencia's likely deputy Matteo Darmian is also injured as Mourinho confirmed in his pre-match interview, but there was no fresh update on the Italian's status on United's website.
"Darmian is also injured. We don't have too many more options [at right-back] and Victor has experience to play in the position even at highest level, in the last Euros he was there for Sweden, so it's not a new position for him," Mourinho explained, as quoted by the Manchester Evening News.
Meanwhile, Smalling will end a run of 13 league starts after the England man struggled with a groin strain late on in the 2-2 draw with Leicester, that resulted in Maguire's goal. Defender Eric Bailly is definitely not taking part as well after undergoing ankle surgery.
In midfield, club captain Michael Carrick is not expected to take part in the hectic festive period while Marouane Fellaini's return still remains doubtful after he strained his knee ligaments while featuring for Belgium in October.