Messi, the Word Player of the Year, faces up to three weeks on the sidelines with a thigh injury he sustained after scoring in a 2-0 victory over Almeria at the weekend.
Fabregas, Neymar and Alexis Sanchez are considered viable options to step in for the Argentine.
"For any team in the world it would be difficult to replace Messi," Martino told reporters ahead of Barca's Champions League meeting with Glasgow Celtic on Tuesday.
"Even for us, though we’ve got a great squad with outstanding players.
"We need to play well, even with him missing. I’m not sure it’s a test to play without him, though we’ve done it before."
Martino continued: "[Fabregas] is great at linking up with the three behind and he sets his team-mates up really well. With Leo we cause the opposition problems in the last 25 metres.
"Neymar also can’t be ruled out, just as Alexis can’t be. We’ve got various options and we’ll see which one is the best.
"It’s not always going to be that when Messi is out Fabregas replaces him."