After guiding his country through 2018 World Cup qualifying, the Spanish manager agreed a three-year deal with Real and lost his job with Spain the following day.
The summer saw Madrid lose Zinedine Zidane, all-time top scorer Cristiano Ronaldo and they look a shadow of the team that's won three Champions Leagues in a row.
The result at Barca, who didn't even have injured captain Lionel Messi, leaves Los Blancos with just one win in their last seven games and ninth in the La Liga table.
The European giants seem to be nearing crisis, and what Lopetegui said to his players after the Clasico humiliation suggests even he knows he could be close to the sack.
Barca destroy Real in first Clasico of the season
Philippe Coutinho's 11th-minute strike opened the scoring, Arturo Vidal headed in the hosts' fifth goal, and in between, Luis Suarez starred with a stunning hat-trick.
Lopetegui tried to change things with a substitution during the interval at 2-0 down, and Marcelo's 50th-minute goal provided an instant effect.
However, they were outclassed by Barcelona for much of the contest, particularly in the first-half, and Lopetegui's days in charge at the Bernabeu may well be numbered.
What Lopetegui said to his players after El Clasico
Marca are reporting that the Real boss said goodbye to his players following the loss at Barca, just in case he loses his job before their next match.
In his post-match briefing, Lopetegui thanked the Madrid squad, he wished them well and showed his appreciation for the four-and-a-half months they've worked together.
The Madrid-based national sports newspaper claim the 52-year-old "knows that he might not see the players again, despite training arranged for Monday".
Is Lopetegui about to get sacked?
We all know how ruthless club president Florentino Perez can be, but Lopetegui's dismissal isn't official yet and he did board the return flight to Madrid.
Real travel to UD Melilla in the Copa del Rey on Wednesday, and should Lopetegui get sacked before then, Castilla manager Santiago Solari is likely to take temporary charge.
Sergio Ramos and Casemiro backed Lopetegui after El Clasico, but only time will tell whether or not he's given a chance to turn this miserable 2018-19 season around.
Do YOU think Real should sack Lopetegui or not? Which manager would YOU bring in to replace him? Have YOUR say in the comments box below!