Messi and Neymar were returning to the starting lineup but the Brazil forward lasted less than 25 minutes as he twisted his ankle turning awkwardly by the touchline and was taken away on a stretcher.
It was Argentina captain Messi's first start since he injured his hamstring last November and he looked sharp in front of goal.
After slotting home his first in the run-up to halftime, he struck again after the break following a trademark mazy run when he hurdled several challenges and a dive by goal keeper Jordi Codina before tucking the ball into the net.
Xavi came on as a second-half substitute for a landmark 700th appearance for Barcelona.
Real Sociedad also progressed with a 1-0 win at Villarreal, having drawn 0-0 in the first leg of their last 16 tie.