Drogba left this summer to join Shanghai Shenhua, and Mourinho believes his departure will hit his former team.
The Portuguese told Sky Sports News: "I believe Drogba is the big difference for them. I don't think you can replace him. You can buy top players and invest like Chelsea did, but there is only one Drogba, in the Premiership and Chelsea's history.
"Drogba means crucial moments. The final, a top match, Drogba is there. When the team is losing at home, Drogba is there. Chelsea will miss Drogba and Drogba will mean a few less points. But the team is good, with good players and they are European champions."