Madrid opened up a four-point gap at the top of La Liga with the win, but it came at a price as Rodriguez limped off after opening the scoring with a diving header after 12 minutes.
Madrid later confirmed the Colombian, expected to be sidelined for around eight weeks, had broken a bone in his foot.
A statement on the club’s official website said: “After the tests carried out on James Rodriguez by the Real Madrid medical services at the Sanitas La Moraleja Hospital, he has been diagnosed with a fracture of the fifth metatarsal in his right foot.
“The player will undergo surgery in the coming hours.”
In what is a huge blow to Los Blancos boss Carlo Ancelotti, defenders Sergio Ramos and Marcelo will also miss the derby trip to Atletico Madrid this weekend.
Ramos limped off with a hamstring problem after only eight minutes of the 2-1 win over Sevilla on Wednesday evening, while left-back Marcelo collected his fifth booking of the season.
Ramos had been substituted after nine minutes with a hamstring problem, but it is unclear how long the defender may be sidelined.
“Sergio had a hamstring problem,” manager Carlo Ancelotti said on the club website. “We cannot evaluate it yet. We must wait a few days.”
Rodriguez’s replacement in the match, namesake Jese Rodriguez, had doubled Madrid’s lead before Sevilla – who themselves lost goalkeeper Beto to injury – replied late on through Iago Aspas.