Howe's side travel to Hillsborough (kick-off 6pm GMT) aiming to book their spot in the fourth round of the prestigious competition and take on Darren Moore's Owls, who currently occupy second place in League One.
Isak, who scored on his Magpies debut away at Liverpool in August, has been named in the starting line-up for the first time since sustaining a thigh injury in September and the leads the line this evening.
Martin Dúbravka, recalled from his loan spell at Manchester United last week, features in-between the sticks for the visitors, the Slovakian's first competitive appearance for Newcastle since May 2022.
The 33-year-old goalkeeper begins behind a four-man defence as captain Jamaal Lascelles, making his 200th competitive start for Newcastle tonight, partners Sven Botman in central defence while Javier Manquillo and Jamal Lewis occupy the respective flanks.
Sean Longstaff and Joelinton, who both played the full 90 minutes against the Gunners at the Emirates Stadium, continue in midfield but the Brazilian could likely return to the middle of the park instead of the left wing.
Elliot Anderson, who made his professional debut for his boyhood club in the Emirates FA Cup third round tie at Arsenal in January 2021, makes his third competitive start of the 2022/23 campaign while Matt Ritchie and Jacob Murphy will aim to provide attacking support for Isak.
Howe has a host of experienced options to select from the substitutes' bench, including the likes of in-form forward Miguel Almirón, Bruno Guimarães, Kieran Trippier and Chris Wood.
There is a place on the bench for Paul Dummett, named in a matchday squad for the first time since October away at Fulham, while Dan Burn, Joe Willock and Ryan Fraser could be deployed from the bench. Karl Darlow is the substitute goalkeeper.
Newcastle United: Martin Dúbravka, Javier Manquillo, Sven Botman, Jamaal Lascelles (c), Jamal Lewis, Sean Longstaff, Elliot Anderson, Joelinton, Matt Ritchie, Jacob Murphy, Alexander Isak.
Substitutes: Karl Darlow, Kieran Trippier, Dan Burn, Paul Dummett, Bruno Guimarães, Joe Willock, Miguel Almirón, Ryan Fraser, Chris Wood.
