Both players left the field on a stretcher during the second quarter of the 20-3 win over Newcastle Falcons in the West Country and were taken to hospital as a result. They both require surgery to correct the damage, Mills to his foot and Simpson-Daniel to his ankle, and are expected to be sidelined for a substantial period.
"Both players are now set to undergo surgery in London on Monday evening," read a Gloucester statement. "A further update on both players will only be issued by the Gloucester Rugby Medical Department once the operations have taken place, and the exact nature of the respective injuries can be fully assessed."
The news is a big blow to Gloucester's Heineken Cup hopes, with their absence robbing the Cherry and Whites of one of their most creative influences and their most experienced performer at a time when their European hopes are very much in the balance.
Ex-England wing Simpson-Daniel has being playing European rugby with Gloucester since 2000/01 and was an Amlin Challenge Cup winner with the club in 2006. He remains a key member of the Gloucester starting XV and is still one of the most potent attacking weapons in the English game as he approaches 60 matches in continental competition.
The 2007/08 English Premiership Player of the Year is just one game short of Gloucester's all-time appearance record currently held by Peter Buxton but he now looks like facing a lengthy wait to pass that mark of 277. Saturday's game was halted for close to 10 minutes while the 31-year-old received treatment on the field after he failed to rise from a tackle after offloading to Mike Tindall and he now faces an anxious wait to find out exactly when he will be able to return to action.
Former England U18 and U20 centre cum fly-half Mills is at the other end of the spectrum in terms of game time for Gloucester but he is highly thought of by all at Kingsholm and is seen as a big part of the club's future aspirations.
Mills may have only played 20 times for the club he joined from Hartpury College via the Exeter Chiefs youth system but he has received plenty of praise and has started both games in this year's Heineken Cup as Gloucester beat Perpignan in Round One before losing at Munster a week later.