Santiago Solari called it a "sporting decision, nothing else" as if that made it better but he was only fanning the flames of what has become his first niggling problem at Real Madrid.
If Isco was injured, his absence from even the substitutes' bench for the Champions League win over Roma on Tuesday would hardly have warranted a second look, but Solari's tactical choice pointed to something deeper.
Solari had not picked him in any of his first five starting line-ups but three times brought him on, against Real Valladolid, Viktoria Plzen and Eibar.
Then, at the Stadio Olimpico, Isco was not involved at all, instead sitting in the stands, dropped beneath the likes of 20-year-old Federico Valverde, 21-year-old Javi Sanchez and 22-year-old Dani Ceballos.
Solari has demoted Keylor Navas fully below Thibaut Courtois in goal but Isco feels like the first marquee player to be significantly worse off under Madrid's new coach.
He underwent an appendix operation towards the end of September but the expected recovery time was only a month. He was also loyal to Lopetegui, who showed faith in him for Spain when Zinedine Zidane was ignoring him at Real Madrid.
"If they sack him, they should sack all of us," said Isco, when Lopetegui's job was on the line last month, a remark quickly rebuked by captain Sergio Ramos.
It has been suggested Solari took note and saw in Isco's comments the kind of cockiness some believe was the cause of the malaise under Lopetegui. But there was no suggestion of that in Italy.
"These are calls that you make in a certain moment," Solari said. "It was a sporting decision, nothing else. There are no guaranteed starters, or substitutes, in football. It is up to all players to be at 100 per cent, to make the coaches pick them."
The implication was a problem with attitude, which Marcelo, speaking close by in the stadium, hardly denied.
"We are all adults," he said. "You have to work. I do not say that Isco does not work but he must work and see why he is failing to play."
Perhaps Lopetegui's departure hit Isco harder than most. He might have felt he finally had a Real Madrid coach that believed in him, only for Solari to take over and put him back on the bench.
When Isco's future has looked uncertain, he has never been short of suitors. Manchester City, Juventus, Liverpool, even Barcelona, were reportedly trying to nab him before his latest contract renewal in September last year.
That deal included a reported release clause of 700 million euros, not a figure usually attached to fringe players, but club support for Isco has not always chimed with confidence from the coach, whether it be Carlo Ancelotti, Rafa Benitez or Zidane.
When he left Malaga for 23 million euros ($26.1 million) in 2013, the sense was Real were adding their own touch of Xavi Hernandez or Andres Iniesta, a Spanish midfielder from the next generation with technique, swagger and an eye for a pass.
But doubts have always lingered around his tactical discipline. A club documentary, 'Heart of the Thirteenth', about last season's Champions League triumph showed Zidane at half-time ordering Isco to play higher up, behind Liverpool's midfield. By the 61st minute, he was being replaced by Gareth Bale.
Questions will be asked again if he is left out of Saturday's La Liga game at home to Valencia, where Real will be hoping to prove their loss to Eibar last weekend was just a blip in an otherwise impressive revival.
Five points still remain between them and Barcelona, in second place, while only six separate the entire top seven, with Sevilla top and Alaves, Espanyol and Girona all well placed.
Atletico will go top if they beat Girona on Sunday but will instantly be leapfrogged by Barca, if the Catalans win at home to Villarreal.
Sevilla will trump both with a victory away to Alaves, a team who have already beaten Real Madrid this season and missed the chance to sit top of the pile when they last Friday. La Liga remains wide open.