The Magpies beat Manchester City in the previous round and will bring 7,000 supporters to Old Trafford, hoping to secure a place in the quarter-finals.
It is the first of three huge games for Newcastle, who are set to host Arsenal in the Premier League on Saturday before travelling to Germany for a Champions League match at Borussia Dortmund.
The Magpies are currently without six first-team players, too. Sandro Tonali is serving a 10-month suspension, while Alexander Isak, Jacob Murphy, Elliot Anderson, Sven Botman and Harvey Barnes are all injured.
In his pre-match press conference, Howe suggested he will make use of the squad: “It’s a busy period for us.