Spain were pegged back by Germany for a 1-1 draw on Friday but Argentina – without Lionel Messi due to injury – fared far worse than the reigning world champions.
Diego Costa put Spain in front, Marco Asensio then adding his second assist of the game by setting up Isco, although Nicolas Otamendi headed one back for Argentina before the break.
That proved a mere consolation for the visitors at the Wanda Metropolitano, though, with Isco on target again shortly after the restart to put Spain in total control.
The Real Madrid playmaker continued to build on an eye-catching individual performance by helping to tee up Thiago Alcantara for Spain's fine fourth, Lopetegui's side sending a warning shot ahead of the World Cup with a fifth via substitute Iago Aspas, who set up Isco to claim the match ball soon after.
Argentina defender Javier Mascherano endured a miserable night to overshadow a proud landmark as he equalled Javier Zanetti's national record of 142 caps, while Jorge Sampaoli's men were shorn of attacking threat in Messi's absence.
142 - Including the game against Spain, Javier Mascherano equals Javier Zanetti as the most capped player for Argentina. Chief. pic.twitter.com/9KrL9fxzYm— OptaJavier (@OptaJavier) March 27, 2018
The visitors should have taken the lead in the eighth minute, Gonzalo Higuain getting in front of Sergio Ramos in the box but cushioning his effort from a left-wing Maximiliano Meza cross wide.
Spain soon punished that miss as Costa scored from close range, although he was hurt in the process by colliding with Sergio Romero.
Andres Iniesta won the ball deep in Argentina territory, with Asensio poking a pass through for Costa to beat Romero to the ball and finish bravely. Both players were initially able to play on after a lengthy delay for treatment, although Romero was then substituted.
Meza almost marked his first international appearance with a goal but Ramos made a fine interception after the debutant swapped passes with Higuain and shaped to shoot.
Spain's greater incision in front of goal saw them double their lead, Asensio playing a perfect low cross for Real Madrid team-mate Isco to slot past substitute goalkeeper Willy Caballero.
3 - Only David Silva (5) has provided more assists than Marco Asensio (3) for Spain in Lopetegui's Era. Mates pic.twitter.com/GGERr7fBqw— OptaJose (@OptaJose) March 27, 2018
Argentina grabbed a goal back in the 39th minute as Ever Banega's left-wing corner enabled Otamendi to beat Ramos in the air and power a downward header through David de Gea's grasp.
Isco restored Spain's two-goal cushion in the 52nd minute. Iniesta's superb lofted throughball sent half-time sub Aspas clear, the striker teeing up Isco for a first-time finish.
Spain were suddenly rampant with Isco turning provider, the midfielder finding Aspas, who touched the ball on for Thiago to slam home.
Ramos appeared to have tucked away another for the hosts, firing in Asensio's cross, but the goal was disallowed for a push, Otamendi then close to a second but seeing his header clip the outside of the post.
Spain are known for possession football but a long De Gea kick down the middle allowed Aspas to add his name to the scoresheet, Caballero beaten far too easily after racing out of his area, with the striker then teeing up Isco to steer home his hat-trick goal.
Tempers threatened to boil over in the closing stages as Argentina lost their composure, while Dani Parejo came off the bench to make his Spain debut and cap a fine night for Lopetegui, whose side look the team to beat in Russia.
For Sampaoli, he can only hope the Messi factor will provide the spark his side clearly needs to be a threat come June.