The 17-year-old, who became the Magpies' youngest-ever Premier League player when he stepped off the bench in the 1-1 draw at Chelsea at the end of last season, will start for his boyhood club for the first time in the third round tie at St. James' Park.
The youngster's inclusion is one of ten changes made by head coach Eddie Howe following the 8-0 win at Sheffield United on Sunday, with only goalkeeper Nick Pope retaining his place from the weekend.
Summer signings Tino Livramento and Lewis Hall will also make their first starts for United, with the former lining up at the back alongside Jamaal Lascelles, Paul Dummett and Matt Targett.
The versatile Hall is in middle of the park along with Sandro Tonali and Miley, while Alexander Isak will head up the Magpies' attack with support from Jacob Murphy and the returning Joelinton on the flanks.
There is plenty of experience on the Newcastle bench, with Kieran Trippier, Fabian Schär, Miguel Almirón and Matt Ritchie all named.
Bruno Guimarães is also among the substitutes, along with Elliot Anderson, Anthony Gordon, Javier Manquillo and Loris Karius.
Newcastle United: Nick Pope: Tino Livramento; Jamaal Lascelles, Paul Dummett, Matt Targett; Lewis Miley, Sandro Tonali, Lewis Hall; Jacob Murphy, Alexander Isak, Joelinton.
Substitutes: Loris Karius, Kieran Trippier, Javier Manquillo, Fabian Schär, Matt Ritchie, Bruno Guimarães, Elliot Anderson, Miguel Almirón, Anthony Gordon.