The Portuguese giants have endured a disappointing campaign under Paulo Fonseca, losing their domestic crown to rivals Benfica while failing to reach the final of either domestic cup and suffering a European exit at the hands of Sevilla.
Former Real Madrid, Barcelona and Rayo Vallecano goalkeeper Lopetegui has replaced Fonseca, who was relieved of duties in March after a string of poor results which included his side's first home league defeat in five years at the end of February.
The 47-year-old has recently been in charge of Spain's national youth teams and has guided the Under-19 and U21 sides to European Championship glory in 2012 and 2013 respectively.
"It is a pleasure and a great honour to be at this club and to defend their magnificent history,2 he was quoted as saying by Uefa.com.
"We will begin by evaluating what happened this season and only after that will we start taking decisions, but we have a philosophy and we want to pass it to the players. We want to challenge in every competition, in every game. And we want players that share that desire."
Porto, having earned 58 points from 29 games, are currently third in the Primeira Liga with one game left to play.