Goals from James Rodriguez and his replacement Jese Rodriguez put the home side in the driving seat at the interval as Carlo Ancelotti’s men went in search of a fifth successive league win.
A late reply from Iago Aspas set up a nervy finish at the Bernabeu but Madrid held on for the points which give them breathing space over nearest rivals Barcelona.
Having put four past Real Sociedad at the weekend, Madrid took just 12 minutes to break the deadlock on Wednesday. Marcelo’s cross from the left found an unmarked James at the far post with the Colombian finding the net from a diving header.
Sevilla should have been level six minutes later after Vicente Iborra rounded home goalkeeper Iker Casillas but his shot come back off the left post.
And Casillas was tested again after 22 minutes by Machin Vitolo, whose 12-yard drive had to be pushed clear by the keeper.
Madrid then suffered an injury setback when James was forced to come off the pitch, making way for Jese.
And Sevilla were beset by their own troubles on the half hour, with Karim Benzema challenging goalkeeper Beto for the ball and catching the keeper on the head with his knee. The Portuguese was down for several minutes before being carried off on a stretcher and replaced by Sergio Rico.
Unfortunately for the substitute, his first action was to pick the ball out of the net within a minute of his arrival. Jese was the scorer, sweeping home from a few yards out despite Isco’s slightly scuffed assist.
The hosts could have had a third moments later but Benzema pushed the ball wide of the right post from what looked to be an unmissable scoring position.
Sevilla continued to feel the heat after the interval and Jese struck the woodwork four minutes into the second half while Isco forced a great save from Rico after 55 minutes as Madrid looked to make the points safe.
Instead it was the visitors who gave themselves a glimmer of hope 10 minutes from time following a spell of patient build-up play around the edge of the area, which resulted in Vitolo picking out Aspas for the striker to turn the ball in from close range.
Madrid’s response was to close ranks at the back as the clock ticked down and the plan worked as Sevilla’s late pressure came to naught.