Spain face European champions Portugal in Sochi on Friday in a clash that caught the eye even before a series of astonishing events unfolded.
Lopetegui was surprisingly named Real Madrid manager on Tuesday and was meant to take charge at the Santiago Bernabeu after the tournament.
But less than a day later he finds himself turfed out of the Spain camp.
The firing of the former Madrid and Barcelona goalkeeper is just the latest reminder of the fine balance any manager of La Roja must strike in the omnipresent rivalry between the country's two biggest clubs.
Julen Lopetegui was fired after taking the job as Real Madrid manager. Photo: AFP
For the first time in a major tournament since 2006, Real's six-strong contingent outnumber Barça players in the Spain squad with only Gerard Pique, Jordi Alba and Sergio Busquets selected, along with Andres Iniesta, who only last month brought his glorious 16-year career at the Camp Nou to an end.
With at least six of the expected starting XI for the Portugal game to come from Madrid and Barça, Hierro, himself a former Real captain, must ensure club loyalties do not further undermine Spain's chances, with divisions already appearing between the players and the federation.
According to Spanish press reports, the players' wish for Lopetegui to stay, including from Pique and Busquets, could not change federation chief Luis Rubiales' mind, so furious was he that Lopetegui had not informed his employers of negotiations with Madrid until minutes before the appointment was
Experienced figures missed
Lopetegui did not lose a single game in 20 matches as Spain boss but even in a flawless qualifying campaign on the field, the Madrid-Barça rivalry and Spain's turbulent political situation overshadowed their performances.
Pique, who will retire from international football after the World Cup, has been jeered routinely by Spain fans for the past two years for his jibes at Real and for defending Catalonia's right to have a referendum on independence from Spain.
The rivalry was often cited as a reason for Spain's tag as perennial underachievers at major tournaments until a golden run of three consecutive victories between 2008 and 2012.
Former Madrid goalkeeper Iker Casillas and Barça captains Carles Puyol and Xavi Hernandez played a big part in binding those squads together and their leadership in the national team has been missed.
Despite his paucity of managerial experience, having spent just one season in charge of second division Oviedo, Hierro could help unify a distressed camp.
He was popular among the players as the federation's sporting director between 2007 and 2011, and returned to that role in November last year.
Games against Iran and Morocco to come in Group B should also give Spain time to recover, even if Portugal do inflict a bad start. Spain bounced back to win the World Cup in 2010 after losing their opening game to Switzerland.
Hierro will also be able to call on one of the most talented squads on show in Russia, with a healthy mix of experience and youth.
Captain Sergio Ramos, Pique, Iniesta and Busquets all have experience of winning major tournaments, while the likes of Koke, Isco and Marco Asensio brought more energy as Lopetegui added fresh blood to Spain in the qualifiers.
He will not be able to complete what he started in Russia but his good work may not go to waste if Hierro can get Spain quickly back on track.