Lopetegui's decision to move to the Santiago Bernabeu despite recently signing an extension with the national team led to a swift departure, with Fernando Hierro taking the helm days before the start of the tournament in Russia.
Spain's dramatic few days off the field caught the headlines and there was similar excitement surrounding their opening game at the World Cup, where Cristiano Ronaldo's late free-kick saw Portugal snatch a point off the 2010 winners.
While the situation has seen some criticism of Lopetegui, Isco says he's happy to see the former national coach take charge of the European champions.
"He's a coach who I've known for many years; we worked together right the way up the Spain set-up. He's given me confidence when I haven't been enjoying a central role at my club, and he's a great coach," he told a press conference on Monday.
Spain have not won their opening game at a World Cup since 2006 and will look for improvements in their upcoming matches in Group B against Iran and Morocco, and Isco believes last week's incidents have brought the squad closer together.
"This team has so much heart, pride and desire to do well," he added. "When the tough gets going, we rise to the challenge. We were dealt a setback and the team got on with it.
"Even when we conceded a goal in the third minute [against Portugal] we refused to go under. This team never gives up."