The Argentine was left writhing in agony after landing heavily on his right arm after colliding with Franco Vazquez.
He was still in obvious discomfort as he left the field in the 26th minute.
Just moments earlier the Barcelona captain had scored a sublime goal to put Barcelona 2-0 up.
Messi had also set up Philippe Coutinho for the opener on two minutes.
Barcelona confirmed after the game that the 31-year-old suffered a “fracture of the radial bone in his right arm” and is set to miss the Champions League tie against Inter Milan in midweek and the clash with Real Madrid next Sunday.
Despite the injury to Messi, Barcelona extended their lead in the second half through a Luis Suarez penalty.
Pablo Sarabia’s deflected long-range effort brought Sevilla back into the game before Barcelona had goalkeeper Marc-Andre ter Stegen to thank for a wonderful double stop to deny first Sarabia and then Wissam Ben Yedder.
Ivan Rakitic’s fine volley made it 4-1 and although substitute Luis Muriel curled home an impressive effort of his own, Barcelona held on to secure their first win in five La Liga matches.
The result also puts them one point clear of Alaves at the top of the table before next week’s huge game at the Nou Camp against rivals Real.
Messi injury overshadows Barca’s return to form
While Barcelona coach Ernesto Valverde will be relieved to see his side end their four-game winless run in La Liga, there will be concern for the fitness of star forward Messi.
The Argentine looked in scintillating form in the opening stages, setting up one goal before scoring a fine second to take his tally for the season to 12 in as many matches.
There is no blame attached to Vazquez as the Sevilla man competed fairly for the ball, but Messi’s full bodyweight landed on his right arm.
The Barcelona physio applied heavy strapping, but Messi was replaced by Ousmane Dembele.
Valverde can take comfort from the form of Luis Suarez, who stepped up in Messi’s absence to put in a commanding display and score his first goal in seven matches.
The former Liverpool striker was a menacing presence throughout and coolly converted a second half penalty to make it 3-0 after he was brought down in the box by goalkeeper Tomas Vaclik.