The Argentine icon sustained a fractured arm after an awkward landing during the win over Sevilla at the weekend, and he has since been ruled out of action for three weeks by the Catalan giants.
He is therefore set to miss a Clasico for the first time since 2007 this coming Sunday, as well as the Champions League double-header against Inter Milan.
He'll miss three others, including the return game against Inter.
The Barcelona superstar will miss playing Inter Milan in the Champions League on Wednesday, and the clasico against Real Madrid next weekend.
"It's a considerable loss", said Barca coach Ernesto Valverde of the injury to his club's all-time top scorer and captain.
Messi was unable to play on though and Barcelona confirmed shortly after full-time tests have revealed a "fracture of the radial bone in his right arm".
Messi created a goal for Phillipe Coutinho and scored Barcelona's second of the game but after a collision with Franco Vazquez he had to be substituted as he could no longer continue due to unbearable pain.
"It was a hard end to the game for us with the goals they scored", Valverde said.
Messi has been in electric form in this season's Champions League.
However, since Messi's debut in December 2004, on the rare European nights where he has not been included, that figure leaps up to 77 per cent with 17 wins in 22 games and only three defeats.