After a difficult start to his career at Real Madrid after joining in 2013, Isco has blossomed under the tutelage of Zinedine Zidane in the past year and took his club form onto the international stage with a virtuoso performance.
His measured free-kick opened the scoring 13 minutes in at a packed Santiago Bernabeu before he doubled Spain's lead with a fierce strike on his weaker left foot just before half-time.
"Playing regularly, gaining important experience with his club and with us means that as a footballer he is growing," said Lopetegui.
"It is one thing to have quality and another to be a great player.
"Isco has always had quality and now he is becoming a great player."
Alvaro Morata came off the bench to round off a perfect night for Spain as they moved three points ahead of Italy at the top of Group G of European qualifying with just three games against Liechtenstein, Macedonia and Israel to go.
"We are happy, not yet satisfied because we are not qualified but happy because the team responded very well against a difficult opponent," added Lopetegui.
"I have always been very satisfied with the response of the players and their mentality and commitment to wanting to be a great team.
"We are on the right track, but we have three more games to go."
Spain's injection of youth since losing to Italy just over a year ago at Euro 2016 was evident.
Isco, Koke, Dani Carvajal and Marco Asensio on his first competitive international start added a spark badly missing as an Italian side managed by Chelsea manager Antonio Conte dominated in a 2-0 win in Paris.
"We've seen a match in which there was a huge difference in the quality and physique of the sides," admitted Italy boss Giampiero Ventura.
And even Ventura was left impressed by Isco's skills as he wriggled free from three Italian players in the second-half with a nutmeg on Paris Saint-Germain midfielder Marco Verratti.
"You only have to see the technical touch, his vision, with the nutmeg on Verratti when surrounded by three players to see he has incredible quality," added Ventura.
"I love moments of technique like that. Even though I am on the opposing side, I have to congratulate him."
Italy are now likely to face a tricky two-legged playoff in November to book their place in Russia next year.
And Ventura claimed it will be hard to close the gap at international level whilst Spanish clubs continue to dominate in European club competition.
Barcelona and Real Madrid have combined to win the Champions League in each of the past four seasons and provided four players each to Spain's starting XI.
"It is simple. You only have to look at almost any Spanish player to see they have played in three Champions League finals and in our side there are very few (with that experience)," said Ventura.
"It is the reality. We need to work step-by-step to improve so that the players can begin to get that same experience."