Magpies boss Eddie Howe admitted, in a pre-match conference, that Martin Dubravka’s fitness is “unclear”.
The goalkeeper failed to train with the Newcastle first team on Tuesday, appearing to join first-choice stopper Nick Pope on the sidelines.
With both his number one and number two seemingly unavailable, Howe could be left with no option but to rely on Karius in his side's crunch clash with Serie A giants AC Milan.
The former Liverpool player has struggled to regain momentum in his career after a tragic defeat in the 2018 Champions League final to a ruthless Real Madrid.
Karius departed Anfield, initially on loan, in the summer of 2018 and made some progress during a spell with Besiktas. In 2022, the German's permanent exit was sealed after his contract with the Reds ran out.
He then joined Newcastle as a free agent, seemingly as the third-choice goalkeeper, behind Pope and Dubravka.
Karius has made just one appearance for the Magpies thus far; their 2-0 defeat to Manchester United in the League Cup final last season.
But a possible story of redemption could be on the cards for the German if indeed Dubravka is unable to make a late return to fitness.
Newcastle find themselves in a precarious position in their Champions League group, level on points with Milan and trailing both PSG and Borussia Dortmund.
Defeat would see the Saudi-backed side crash out of Europe's elite competition, but a draw would see them drop into the Europa League.
Victory over Milan is required to progress in the Champions League, but it doesn't guarantee as much.
If PSG are able to beat Dortmund in their final group match, the Parisians will progress instead of the Magpies.
But if Dortmund, the group leaders, are able to hold off PSG, it paves the way for Newcastle to leapfrog the Qatari-backed outfit into the knockouts.