Pique has accumulated 102 caps for his national team, a record that coincides with the most successful period in Roja history.
Among the centre-back's international honours are the 2010 World Cup and a Euro 2012 winner's medal.
But his international career has rarely been smooth sailing, with his outspoken support of Catalan nationalism often a stick with which Spain fans have used to criticise him.
And despite the presence of former Barca boss Luis Enrique on the Spain bench, Pique has decided to call it a day.
"I have had a really good time, with a European Championship and a World Cup, but that story is at an end," he told reporters on Saturday prior to Barcelona's Supercopa clash with Sevilla.
"I have told this to Luis Enrique."
Even before the World Cup, Pique had hinted that Russia 2018 would be his last major tournament as part of La Roja.
"It would make sense to leave it after the World Cup," he had signalled.
"It has been a wonderful time and I have experienced amazing things, but sometimes you have to end cycles and you have to do that in the right fashion."
Pique joins former Barcelona team-mate Andres Iniesta, who also announced his international retirement in the wake of July's last-16 elimination at the hands of hosts Russia.