Karanka worked as Mourinho's second-in-command during his time as manager of Real Madrid, before receiving a glowing recommendation from his former employer as he applied for the vacant Boro job in 2013.
It will be the first meeting between the two on opposing sides but, while the managers plan to share a drink after the game, each side is in need of a win and proceedings are unlikely to be overly friendly.
United will be without captain Wayne Rooney as he continues to struggle with a thigh problem, meaning Henrikh Mkhitaryan should keep his starting place.
Luke Shaw is also absent through injury, with United otherwise coming into the New Year with a mostly clean bill of health.
Middlesbrough will be forced into a re-shuffle at the back due to right-back Antonio Barragan's one-match suspension, with Calum Chambers, former United man Fabio, or Emilio Nsue the most likely candidates to take his spot on the right.
Viktor Fischer is also out of contention with a knee injury, with Boro likely to field an attacking trio of Alvaro Negredo, Gaston Ramirez and Adama Traore.
Though United unsurprisingly have the better record of the two sides in head-to-head meetings with 62 wins to Boro's 34, Middlesbrough won the last encounter in a League Cup penalty shoot-out in Manchester last season.
Indeed, Middlesbrough's record against United is far from poor - they have scored three goals at Old Trafford on three occasions in the Premier League era, more than any other visiting side.
However, United are unbeaten in the last seven league meetings between the two sides, with four wins and three draws since Boro's last league victory in October 2005.
Speaking to the club's official website ahead of the game, Mourinho claimed that Manchester United's team spirit is having a hugely positive impact on his side's performances.
"The team spirit I see is just fantastic," he said. "It is getting better every single day and I think that is showing in the way we are playing, because some of the football we have produced in recent weeks has been very good.
"We have been playing well for a long time but it was important that we started getting the points that our performances deserved. Now that we are, it is up to us to maintain that momentum with more good victories."
Meanwhile, Karanka told Boro's official site that his first ever clash with Mourinho was one of the first fixtures he looked out for when they were announced before the start of the season.
“The second one [I looked for after the opening game] was Man United," Karanka admitted. "It will be a special moment for me and for my players.
“For my team, I know what a great stadium Old Trafford is and how nice it is to play there. I spent three amazing years with Jose at Real Madrid and I learnt something from him every day. He is one of the best in the world.
“But it’s football and the points are really important for us. For those 90 minutes you can’t be friends. We will share a glass of wine or beer after the game, but no doubt one of us will be happier than the other.”
Manchester United are hoping to keep the heat on at the top of the table, but with a 13-point gap separating themselves and leaders Chelsea, they will likely have to settle for the chase for the top four.
A win this weekend could see them move above Tottenham Hotspur if Spurs slip up at Watford, while at least one of Liverpool and Manchester City will drop points as they face off at Anfield.
Meanwhile, a surprise win for Middlesbrough could see them climb as high as 12th if results elsewhere go their way, though Crystal Palace and Leicester City could both leapfrog the Teessiders with wins.
Boro host Leicester in a crucial game at the bottom of the table just two days after they travel to Old Trafford, meaning Karanka could opt to rest some key players during the Saturday game.