Spain were heavy favourites to beat hosts Russia in Moscow on Sunday but were defeated 4-3 on penalties after a 1-1 draw at the Luzhniki Stadium.
Isco was one of five Spain players to attempt over 100 passes as Russia progressed to the quarter-finals despite having a solitary shot on target and just 17.5 percent possession in the second half.
The Real Madrid star, though, said Spain have to bounce back from their last-16 exit.
“Today is the saddest day of my career…” Isco posted on Instagram.
“But that’s football and it doesn’t stop… life doesn’t stop… it’s time to pick ourselves up like we’ve done before… proud to represent this country.”