The Magpies head to Wembley without first choice goalkeeper Nick Pope who is serving a suspension after his red card against Liverpool last weekend.
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Back-up goalkeeper Martin Dubravka also sits out the Wembley showpiece due to being cup-tied after his loan spell at Old Trafford earlier this season.
That leaves Karius to make what will be his first competitive game in two years and his first for a Premier League side since his nightmare display for Liverpool in the 2018 Champions League final.
Bruno Guimaraes makes his return to the starting line-up after completed a three-match suspension, while Joelinton and Sean Longstaff also start for the Magpies.
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Manchester United boss Erik ten Hag has Marcus Rashford available after he limped off in Thursday's Europa League win over Barcelona.
The 25-year-old has been in blistering form this season and has netted in seven of his last eight games in all competitions.
Rashford has scored 24 times this season and is key to United's attacking threat and was fit enough to start.
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Christian Eriksen and Donny van de Beek remain long-term injury absentees for the Red Devils.
Both club's will be hoping to end their trophy drought with Ten Hag and Howe eyeing their first piece of silverware as they aim to kick-start a new era.
Howe is tasked with leading a Newcastle side to a first major trophy since 1955, when they beat Manchester City 3-1 in the FA Cup final.
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A win for the Magpies would propel Howe into club folklore and the hearts of a fanbase starved of success.
Ten Hag, can cap off a superb maiden season in charge with a first trophy at the club.
His side are still in the mix to lift the Premier League title, FA Cup and Europa League.
United are without a trophy since their Europa League win over Ajax in 2017 and a win against Newcastle would be their first EFL Cup triumph since the 2016-17 season.
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Man United XI: De Gea, Dalot, Varane, Martinez, Shaw, Casemiro, Fred, Antony, B.Fernandes, Rashford, Weghorst.
Subs: Heaton, Lindelof, Maguire, Wan-Bissaka, Malacia, McTominay, Sabitzer, Garnacho, Sancho.
Newcastle XI: Karius, Trippier, Schar, Botman, Burn, Guimaraes, Longstaff, Joelinton, Almiron, Saint-Maximin, Wilson.
Subs: Gillespie, Lascelles, Ritchie, Targett, Isak, Manquillo, Murphy, Willock, Anderson.