The 31-year-old hinted prior to this summer's World Cup that the tournament would be his last for La Roja, and he has now officially announced that he will no longer make himself available for selection under new Spain boss Luis Enrique.
Pique has often been booed by Spanish fans while playing for the national team due to his outspoken views on Catalonia, where he plays his club football for Barcelona.
However, the former Manchester United defender insisted that he felt "fortunate for being a part of the national team during such a beautiful and successful time" and said "the decision had already been made a long time ago and it was well thought out".
Pique retires having made 102 appearances for his country, winning 73 of those since his debut in 2009.
The Barcelona man is one of 13 players to have reached a century of caps for Spain and was a key player in their victories at the 2010 World Cup and Euro 2012.