And it has been confirmed by Spanish champions Barcelona that their superstar will be out of action for the next three weeks.
Messi was taken to a clinic and the club said tests showed a "fracture of the radial bone".
The doctors wrapped his elbow with bandages and the playmaker tried to continue, but he eventually left the field. Luis Suarez added the third by converting a second-half penalty kick.
Sevilla midfielder Pablo Sarabia pulled a goal back for the visitors soon after, helped by a heavy deflection from Barca defender Clement Lenglet, only for former Sevilla skipper Ivan Rakitic to score Barca's fourth, declining to celebrate the strike against his former club.
"Of course it changes things for us, but it is a challenge for us to cover for him", Valverde said.
Coutinho scored after two minutes against Sevilla and will be relied on to deliver against Inter.
Sevilla beat Real Madrid with those same weapons, but the difference between playing at home at the Estadio Sanchez Pizjuan and going to the Camp Nou is massive. The Catalans are four points ahead of stuttering Real, whose problems deepened with a 2-1 defeat at home to Levante. Borja scored a goal in each half in Espanyol's 2-0 win away to Huesca, whose new coach Francisco debuted with a defeat after replacing Leo Franco during the worldwide break.
As Gareth Bale and Karim Benzema struggle to find the net, Lopetegui could do with a hero of Ronaldo's ilk for the trip to Catalunya. It still created enough chances, striking the woodwork three times and having a goal by Mariano Diaz disallowed for offside in the final minutes.
Madrid finished with 70 per cent possession and more than 30 attempts. Barcelona, meanwhile, seem to have sparked a rival.
Inter and Barca have won their opening two games heading into matchday three and Icardi believes the Serie A side can go toe-to-toe with the LaLiga champions in the absence of Messi.
It is six games since Barca last kept a clean sheet - a 4-0 rout of PSV Eindhoven in their Champions League opener - and the defence has come under scrutiny amid the poor run.