Much of the talk heading into the game had centered on the absence of Lionel Messi and Cristiano Ronaldo from the fixture for the first time in 11 years – with the Barca skipper missing out through injury and Ronaldo now playing for Juventus.
But Suarez stepped spectacularly into the void to mean the biggest storyline to emerge from an ultimately resounding defeat will now be Lopetegui’s future, as Real’s worst start to a season in 17 years was compounded by their greatest rivals.
If the Real players had been fired up before the game to save their ailing manager, they certainly didn’t show it as they found themselves behind after 11 minutes, when Philippe Coutinho swept home from a Jordi Alba cross as Real were caught cold on the counter attack.
Barcelona continued to look the more dangerous of the two teams in front of 93,000 fans at a typically raucous Camp Nou, with Alba in particular posing a menace on the left as Karim Benzema cut an isolated figure up front for Real.
The Catalans doubled their lead from the penalty spot on 30 minutes, when Suarez went down under pressure from Raphael Varane. The spot-kick was given after referee José María Sánchez Martínez consulted VAR – the first decision of its kind in El Clasico.
The Uruguayan picked himself up to dispatch the penalty past a departing Thibaut Courtois. Suarez celebrated by unveiling a T-shirt tribute to his new-born son – fitting given it was largely child’s play for Barca at that point.
The hosts continued to dominate, with Real restricted to long rage efforts from Gareth Bale, Marcelo, and skipper Sergio Ramos – none of whom troubled Marc-André ter Stegen.
Perhaps sensing the could be playing out their final half of football under Lopetegui, Real roused themselves after the break.
Marcelo pulled one back on 50 minutes by poking home from eight yards after Barca failed to clear a cross, showing Los Blancos were not ready to raise the white flag.
Luka Modric then rattled the post and saw the ball roll agonizingly along the goal-line as Real pressed and the game began to live up to its billing as club football’s biggest contest.
As the men in white threatened, they almost got caught cold when Suarez saw a shot blocked by Marcelo and deflected onto the post from close range.
Benzema headed over when unmarked as the game looked like it could swing either way.
But Suarez sucked the life from Real with a brilliant flicked header home from Clement Lenglet on 75 minutes, before sealing a resounding win for the Catalans with delightful chip ten minutes later – potentially sealing Lopetegui’s fate with it.
Substitute Arturo Vidal added a fifth when he headed home with three minutes to play, sending Barca fans into raptures and an abject Real further into despair.
The result means Barca sit top of La Liga, while Real languish in ninth and Lopetegui teeters on the edge of an early departure from the Real hot seat he secured in such controversial circumstances in the summer.