Andres Iniesta finished off a fine team move to add a third after the break.
Suarez's cool finish wrapped up the win before Isco was sent off for a rash challenge to complete Real's misery.
It was a first home defeat in 23 league games for Real, but an early blow to their hopes of challenging Barcelona for the title this season.
Rafael Benitez's side are second with 24 points with Barcelona moving onto 30 points after 12 games.
No Messi, no problem
The Argentina forward, Barcelona's leading goalscorer, was named on the bench for the first time since suffering a knee ligament damage on 26 September.
However, in his absence Suarez and Neymar have been in phenomenal form, combining to score all 17 of Barcelona's goals since Messi's injury, and the pair were in deadly form once again on Saturday.
That was only the second goal Real had conceded at home all season, but their usually strong defence simply had no answer to Barcelona's attacking prowess.
Iniesta's smart ball set Neymar free, and the Brazilian made no mistake for the visitors second.
Following Iniesta's drive high into the net, Barcelona boss Luis Enrique introduced Messi, who marked his return by playing a part in Suarez's second.
What went wrong for Real?
After suffering their first defeat of the season against Sevilla in their previous fixture, Real Madrid fans will have expected an improved display in the first El Clasico of the campaign.
It never materialised. The hosts managed just one shot on target in the first half, while Cristiano Ronaldo was quiet for much of the game.
The Portuguese forward did manage to force Barcelona goalkeeper Claudio Bravo into a smart save in the second half, but by then it was too late.
Isco's late lunge on Neymar, which earned the midfielder a red card, summed up their frustrations.
"I've been really disappointed by Real Madrid," added Waddle. "There are too many egos. Barcelona are a team, they work as a unit. Real don't."
Man of the match - Andres Iniesta
The stats you need to know
- Barcelona have recorded their second biggest win without conceding in a league away game against Real Madrid (5-0 in 1974)
- They won 4-0 in a league away game against Real Madrid for only the second time in Clasico history (4-0 in Copa de la Liga in 1986)
- Luis Suarez has scored or assisted in his three games against Real Madrid (three goals, one assist)
- The last player sent off in a Clasico at Santiago Bernabeu was Sergio Ramos on 23 March 2014
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