A late Iago Aspas goal was merely a consolation for Unai Emery's men as Carlo Ancelotti's side restored its four-point lead at the top.
La Liga pacesetter Real Madrid extended its lead over Barcelona to four points by beating wasteful Sevilla 2-1 at the Santiago Bernabeu on Wednesday.
Carlo Ancelotti once again had to do without the suspended Cristiano Ronaldo, but his men were in clinical form against Unai Emery's side, with first-half goals from James Rodriguez and Jese Rodriguez enough to win a frantic encounter.
Despite falling behind to James' 12th-minute header, Sevilla arguably enjoyed the better of the first half-hour, as Vitolo, Vicente Iborra and Grzegorz Krychowiak all went close to finding the net.
Knocks to Sergio Ramos and James forced Ancelotti into changes, while the first half was marred by a potentially serious head injury suffered by Sevilla goalkeeper Beto in a collision with Karim Benzema.
Real showed no mercy, though, doubling its lead through Jese just one minute after Beto's exit, giving Sevilla - which lost 7-3 on its last visit to the Bernabeu - a mountain to climb.
Iago Aspas pulled one back with 10 minutes to go, after Jese had been denied a second goal by the woodwork, but Real held on to open up a healthy advantage in the Liga title race.
Sevilla began the contest brightly and should have taken the lead inside three minutes, as Vitolo capitalized on a defensive miscommunication, only to see his effort smothered by the advancing Iker Casillas.
The visitors then received a boost to their chances in the ninth minute, as former Sevilla defender Ramos was forced off after seemingly injuring his hamstring.
That substitution showed no signs of causing an immediate hindrance to Real, though, and James put them into the lead three minutes later, meeting Marcelo's pinpoint delivery with a diving header.
Sevilla did not look perturbed by falling behind and almost hit back four minutes later, as Iborra charged into the area and hit the post, before Krychowiak headed into the side-netting soon after.
Stoppages began to upset the away side's momentum, however, with goal-scorer James forced off, before Sevilla goalkeeper Beto required a stretcher after being caught on the head by Benzema's knee in the 35th minute.
Within 60 seconds of Beto's withdrawal, substitute keeper Sergio Rico was picking the ball out of his net, as James' replacement, Jese, smashed in from close range.
Sevilla continued to see its fair share of possession early in the second half, but Real looked rampant going forward and a crucial Krychowiak block prevented Gareth Bale from scoring a fine solo effort, before Jese fired against the post from an acute angle.
Isco also got in on the act, driving through the middle of the Sevilla team in the 55th minute, only to see Rico produce a good save.
The visitors remained a threat on the break and should have clawed one back with half an hour to go, but Iborra inexplicably missed the target from six yards.
Emery furiously urged his men forward in search of a last-gasp comeback and substitute Aspas steered past Casillas following Vitolo's delightful run and cut-back, but they failed to find a second and Real secured a slender win to go four points clear at the summit, while Sevilla stay fourth.