The victory leaves Los Blancos level on points with Barcelona at the top of the division, but Real have a game in hand.
First-half goals from Nacho and Cristiano Ronaldo gave Madrid a strong lead at the interval as the traveling side struggled to find form and fluidity.
Stevan Jovetic hit back for Sevilla early in the second half, but replies from Ronaldo and Toni Kroos crushed the visitors' intentions.
Madrid rang the changes as Marcelo, Casemiro, Luka Modric, Isco and Karim Benzema were replaced by Nacho, Mateo Kovacic, Marco Asensio, James Rodriguez and Alvaro Morata.
Nico Pareja, Matias Kranevitter, Daniel Carrico, Joaquin Correa and Stevan Jovetic were new additions to the starting XI for Sevilla as they rotated their side.
Real claimed the lead in bizarre circumstances after 10 minutes as Nacho converted a quick direct free-kick to cause Sevilla embarrassment.
The 27-year-old defender took advantage of the visitors' lack of awareness as they stood with their feet planted to floor, allowing the Madrid player to beat goalkeeper Sergio Rico.
Sevilla players appeared stunned by Nacho's effort, but the referee had no hesitation in awarding the opener.
Journalist Sid Lowe questioned the fairness of the strike:
Ronaldo doubled the lead after 23 minutes as Sevilla failed to contain the Galacticos legend.
Sergio Rico saved a shot from James Rodriguez, but the Portugal attacker was on the spot and ready to force the ball home.
WhoScored.com provided the vital statistics at half-time as Real controlled proceedings:
Sevilla fired their way back into the match just four minutes into the second half as Jovetic's smart finish beat 'keeper Keylor Navas.
The attacker's curling effort gave the Madrid No. 1 no chance, offering Los Nervionenses a route back into the game.
There was a distinct nervousness creeping into the atmosphere of the crowd as Los Blancos struggled to keep their foot on the gas, and manager Zinedine Zidane responded by replacing James with Casemiro.
James took his time to leave the pitch as the home fans applauded what could be one of his final appearances for the club, per Guillem Balague of Sky Sports.
The tension was released by Ronaldo with 13 minutes to play as the forward blasted a sensational strike into the top corner, and the Bernabeu exploded into song.
Zidane celebrated in the technical area as the goal gave the hosts the breathing space they craved.
Lowe called the action as the third hit the back of the net:
In the closing stages, midfielder Kroos completed a lightning-fast move from the hosts to make it 4-1 and put the game to bed.
Sevilla were well beaten as the contest ended, and Madrid maintained their La Liga title lead.