United face the Liga leaders over two legs for a spot in the semi-finals of the Champions League, having stunned Paris Saint-Germain with a last-gasp away-goals win in the French capital to reach the last eight.
Cole, a European champion in United's 1998-99 treble-winning season, cited the danger that Messi represents to the club's hopes of getting their hands back on the famous trophy.
"They've got a little magician in their team and, if he turns up, I'm not going to say 'we need to mark him out of the game' because you can't," the 47-year-old told United's official website.
"If he decides he's going to play and if he doesn't, he'll still play [well], he's that good. We'll have to wait and see."
Barca are clear favourites to triumph, but Cole believes Ole Gunnar Solskjaer's side can cause an upset if they stick to their principles.
"Anything's possible," he said ahead of Wednesday's first leg at Old Trafford. "We weren't expected to get past PSG but we did that. But we know Barcelona are a very good and special team.
"I think what we can do is play the way Manchester United should play.
"We did that when we won the Champions League in 99, we played Barcelona twice and both legs ended 3-3, with both teams playing attacking football which we're used to. We have to do exactly that."
Messi has been in scintillating form of late, bagging nine goals in his last five appearances for Barcelona.
He poses a huge threat on the European stage as well, with the Argentina international already scoring eight times in this year's Champions League despite also only starting five matches.
Barcelona and Manchester United meet in the first leg of their encounter on April 10.
But before then, Ernesto Valverde's side host Atletico Madrid in a much-anticipated Liga title encounter which could potentially derail the Catalan club's hopes of winning the competition.
If the Madrid side win, they will be just five points behind Barca.