Asked if Hazard can replace the Portugal superstar, Messi told Marca's Luis F. Rojo: "Hazard has a lot of quality. He is a different football player who can unbalance [defences], but I think he is different to Cristiano, with different characteristics. It is very difficult to replace Cristiano, but Hazard is also a great player."
The Belgian is set to miss his first Clasico after he suffered a microfracture to his ankle in Real's 2-2 UEFA Champions League draw with Paris Saint-Germain on November 26.
Hazard has scored just once for Los Blancos, as well as contributing four assists in his 13 appearances, but his performances prior to his injury had been improving, so his absence will be a blow to Real Madrid.
Barcelona have won eight and lost just three of their 14 meetings with Real in all competitions since the start of 2015. However, they've only won one of Real's last six visits to the Camp Nou, where they'll play on Wednesday.
Messi was also asked why Barca tend to fare better against them in the Spanish capital than at home:
"When we play at the Bernabeu, many more spaces are generated. They attack us more because they have the obligation as the host team and people push them for that.
"At the Camp Nou they play another type of match, sitting a little further back, they are closer together and hit on the counter-attack because they have very fast players upfront."
The Argentinian added that at the Camp Nou matches are more "locked" and "complicated."
Messi has an impressive record against Madrid, having notched 26 goals and 14 assists in 39 appearances against them.
He hasn't been as strong against them of late, however:
Squawka's Muhammad Butt observed their struggles when he's not at his best:
He has had an excellent season, though, with 14 goals and nine assists in 16 games in all competitions.
Messi plundered a fine hat-trick against Real Mallorca on December 7:
If he's on that kind of form, Real stand little chance of coming away with a win on Wednesday.
Suarez has been in productive form, too, having offered up four goals and five assists in his last six outings. Antoine Griezmann has three goals and an assist in his last five games, which is an improvement on his form prior to November's international break.