The Uruguay striker is set to make his first appearance since receiving a four-month ban for biting Italy's Giorgio Chiellini at the World Cup.
Lots has happened since Suarez's moment of shame, most notably his reported €94million switch from Liverpool to Barcelona, and he will be desperate to repay the faith shown in him by the Catalan giants with a debut goal.
The fact that Suarez's landmark appearance comes in the biggest game of club football in the world is a script writer's dream - but there will be plenty of other stars on show at the Santiago Bernabeu.
Lionel Messi, for example, can become La Liga's all-time leading scorer with a brace, while Real talisman Cristiano Ronaldo is rarely out of the headlines.
Throw Neymar, James Rodriguez, Andres Iniesta and Karim Benzema into the mix and you have a fixture that will draw the attention of the world.
Barca lead the league by three points and will be buoyed by the fact they did the Liga double over Real last term, including a 4-3 road win that was a genuine classic.
Both sides enter the 229th El Clasico off the back of UEFA Champions League wins, but Real will be without Welsh star Gareth Bale, who misses out with a gluteal injury.
Second-placed Sevilla may enjoy the lack of attention on them this weekend as they host Villarreal on Sunday.
Unai Emery's men - inspired by the six goals of striker Carlos Bacca - have won six of their eight matches this season.
Villarreal will arrive in Seville in good form, though, having secured consecutive victories to climb to sixth.
Sevilla can go level on points with Barcelona if they win and Real claim all three points in El Clasico.
Last season's champions Atletico Madrid visit Getafe as Diego Simeone's men seek to keep pace with the chasing pack, knowing a win could take them up to second.
Fourth-placed Valencia should have few problems at home to Elche, who sit in the relegation zone.
Granada will be out to arrest a run of four straight losses at Eibar - who have not won in four themselves.
Cordoba have a good chance to move away from the foot of the table when they host Real Sociedad, who have not won since August.
Elsewhere, Celta de Vigo host Levante on Friday, while Almeria battle Athletic Bilbao and Rayo Vallecano visit Malaga.
And Deportivo La Coruna - who ended a run of four straight losses, in which they shipped 15 goals, with victory over Valencia last time out - hit the road to play Espanyol.
