The England midfielder was in line to feature for the Rossoneri in their crunch Serie A clash.
However, that plan quickly changed when Loftus-Cheek was taken to hospital to have his appendix removed.
It comes after he felt severe abdominal pain in his stomach overnight.
It’s unclear how long the 29-year-old will be ruled out for.
Loftus-Cheek had been hoping to play a key role for AC Milan against Napoli after making his comeback from injury against Como last week.
He was even tipped to start with Yunus Musah suspended for the clash.
After returning from injury, Loftus-Cheek trained over the international break and even traveled with the team before noticing that something was wrong.
After being taken to a local hospital he was diagnosed with appendicitis.
The condition happens when the appendix becomes inflamed. It can be fatal, if left undetected and the appendix bursts.
The 29-year-old had been out of action since mid-December with a muscle injury and was on track to start in Naples.
Loftus-Cheek has played 22 times for AC Milan this term, but has been limited to just seven starts in all competitions due to injury.
Having moved to the San Siro for £18.5million in the summer of 2025, Loftus-Cheek has made a big impression.
He has 10 goals and three assists in 62 matches for the Italian giants.
While at Chelsea, Loftus-Cheek made 155 appearances for the first team while also winning 10 senior caps for England.
Unfortunately things haven’t gone to plan for AC Milan this term.
It’s been a disappointing season for Milan who saw previous boss Paulo Fonseca sacked in December.
He was replaced by Sérgio Conceição with the club currently sitting ninth position in Serie A.
That’s 14 points behind Napoli who are challenging Milan’s rivals, Inter, for the Italian title.
