Del Bosque left the role following a disappointing Euro 2016 campaign and now Lopetegui, the former Porto head coach, will look to guide the country towards qualifying for the 2018 World Cup.
Lopetegui has managed Spain at Under-19, Under-20 and Under-21 level - winning the European Championships with the Under-19s and Under-21s - and has now made the step up to the senior side.
Lopetegui guided Porto to the Champions League quarter-finals during the 2014/15 season but a poor run of form last season led him being dismissed in January.
The 49-year-old former goalkeeper, who was on the books at both Real Madrid and Barcelona during his player career, will take control of his first game in September, in a friendly against Belgium.
Lopetegui was recently linked with taking over the reins at Championship side Wolverhampton Wanderers prior to being named as Del Bosque's successor.