Messi suffered a tear in the medial collateral ligament of his left knee during Saturday's 2-1 win over Las Palmas and looks set to miss Barca's next eight games.
"A player like Leo is irreplaceable," Luis Enrique said on Monday ahead of his side's return to Champions League action at home to Bayer Leverkusen on Tuesday.
"In pre-season none of Leo, Neymar or (Luis) Suarez played, but our idea of how to play didn't change. It is a challenge for us to be without the best player in the world, but it also provides an incentive for us."
However, Luis Enrique is confident the 28-year-old will be fit for Barca's first meeting with Real Madrid this season on November 21 at the Santiago Bernabeu.
"Leo came in yesterday for the medical check-up and he looked good, he was in high spirits," added the coach.
"Time is in his favour."
Midfielder Ivan Rakitic is also hopeful that Messi's absence will act as a spur for his teammates to take more responsiblity in the coming weeks.
"We hope he returns as soon as possible."
Barca were held to a 1-1 draw in their first Champions League game of the campaign away at Roma a fortnight ago and Luis Enrique insisted it is imperative they get all three points against group leaders Leverkusen at the Camp Nou.
"I don't know if Leo's absence will be a boost for Leverkusen, but for us it is a key game against one of the strongest opponents in the group.
Despite the body-blow of Messi's absence, there is some good news on the injury front for Barca as both goalkeeper Claudio Bravo and left-back Jordi Alba trained on Monday and are expected to be available for selection.
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