As expected, head coach Enzo Maresca has named an entirely different starting lineup from the Blues side that began the 2-1 win over the Magpies in the Premier League on Sunday afternoon.
Marc Cucurella and Enzo Fernandez are back in the first XI, as are the likes of Joao Felix and Christopher Nkunku.
Renato Veiga gets the nod in central midfield, rather than Cesare Casadei who may have expected to be handed an opportunity against top-flight opposition.
Axel Disasi is included at right-back, with Josh Acheampong not being considered while he is still in contract negotiations with the club's board.
Kiernan Dewsbury-Hall appears in line to feature on the right-hand side, but there is no place in the squad for Jadon Sancho despite receiving no game time in the last two matches.
Ben Chilwell, Carney Chukwuemeka and Marc Guiu will all hope for opportunities from the substitutes' bench.
Gordon returns
Meanwhile, the big talking point for Newcastle is Eddie Howe being able to call upon Anthony Gordon, who missed out with a groin injury at the weekend.
There are a further four changes to the side that lost at Stamford Bridge, including Emil Krafth and Lloyd Kelly being brought into the defence.
Sean Longstaff and Joe Willock start in midfield and attack respectively, while there is the return to the substitutes' bench of Lewis Miley who has been out in the long term with a back injury.
Newcastle United XI: Pope; Krafth, Schar, Kelly, Hall; Joelinton, Tonali, Longstaff; Gordon, Isak, Willock
Subs: Dubravka, Barnes, Osula, Livramento, Almiron, Burn, Murphy, Guimaraes, Miley
Chelsea XI: Jorgensen; Disasi, Tosin, Badiashile, Cucurella; Veiga, Fernandez; Dewsbury-Hall, Joao Felix, Mudryk; Nkunku
Subs: Bergstrom, Bettinelli, Colwill, Chilwell, Casadei, Chukwuemeka, Madueke, Palmer, Guiu