With regular skipper Bruno Fernandes named on the bench, the Brazilian returned to captain Erik ten Hag's side in the fourth round of the Carabao Cup on Wednesday night, having been sidelined of late with suspension followed by an ankle problem suffered on international duty last month.
However, he struggled in another dismal 3-0 home defeat that meekly ended United's defence of their first major trophy for six years and piled more pressure on his under-fire manager.
Casemiro was booked for an early couple of sluggish fouls on Joe Willock and alongside the disappointing Mason Mount and young Hannibal Mejbri struggled to contain Newcastle's energetic midfield.
The former Real Madrid stalwart then went off alongside the similarly under-par Diogo Dalot, with Ten Hag sending on Sofyan Amrabat and the fit-again Aaron Wan-Bissaka at the break.
Ten Hag has since confirmed that Casemiro came off due to injury and will remain sidelined for Saturday's lunchtime trip to Fulham in the Premier League.
He did not specify exactly what issue was now troubling the 31-year-old and is uncertain at this stage how much more time he stands to miss.
"He was injured," Ten Hag said when asked why he hooked Casemiro at the break against Newcastle.
"Just before half-time, that is why we have to take him off."
Pressed on how long he could be without the Brazilian after this latest setback, Ten Hag added: "I can’t give an answer; we have to wait 24 hours, but I think definitely for Saturday he is out."