The Sweden international was finally granted international clearance to play on the day of the game, having been ineligible for Sunday's draw at Wolves, and goes straight into Eddie Howe's side as one of four changes.
Jamaal Lascelles comes in to captain the team, while Matt Targett and Ryan Fraser also start, with Allan Saint-Maximin ruled out with a hamstring problem.
Nick Pope is in goal, with Kieran Trippier at right-back, Lascelles partnering Dan Burn in central defence and Targett on the left of the defence.
Sean Longstaff, Joelinton and Joe Willock continue in midfield with Fraser and Miguel Almirón supporting Isak, who will become the 255th man to represent the Magpies in the Premier League.
Sven Botman and Fabian Schär are both on the bench, where they're joined by Karl Darlow, Jamal Lewis, Matt Ritchie, Javier Manquillo, Jacob Murphy, Elliot Anderson and Chris Wood.
Newcastle United: Nick Pope, Kieran Trippier, Jamaal Lascelles (c), Dan Burn, Matt Targett, Joelinton, Sean Longstaff, Joe Willock, Miguel Almirón, Ryan Fraser, Alexander Isak
Substitutes: Karl Darlow, Javier Manquillo, Jamal Lewis, Matt Ritchie, Sven Botman, Fabian Schär, Jacob Murphy, Elliot Anderson, Chris Wood