Francisco Román Alarcón Suárez aka Isco fired-up Argentina with a hat-trick that saw the Spanish team lead with 6-1 in a friendly match victory as countries prepare the anticipated 2018 FIFA World Cup in Russia.
Diego Costa put himself in harm's way to slide in Spain's opening goal 12 minutes in, and was injured after colliding with Argentina goalkeeper Sergio Romero.
The former Chelsea striker looked in some pain, while Manchester United back-up Romero was also forced off soon after.
Isco put Spain in control with the second of the game after just 27 minutes, but Nicolas Otamendi gave Argentina - without talismanic captain Lionel Messi - hope with a goal shortly before half-time.
But Argentina faded badly after the break as Isco scored two more to complete his hat-trick either side of goals from Thiago Alcantara and Iago Aspas to show the South American nation just how much pressure rests on Messi's shoulders in Russia this summer.
Barcelona playmaker Messi had been expected to return after missing Friday's 2-0 win over Italy in Manchester as a precaution because of an abductor muscle injury.
However, concerns over what is also said to be a hamstring problem meant the Albiceleste captain was conspicuous by his absence when the teams were named at the Wanda Metropolitano Stadium.
Argentina, also without Manchester City forward Sergio Aguero because of a knee problem, should have gone ahead in the eighth minute.
Maximiliano Meza charged down the left and clipped the ball back across the six-yard box, but Juventus forward Gonzalo Higuain somehow stabbed his shot off target.
It proved a costly miss as Costa fired Spain in front after 13 minutes.
The Atletico Madrid forward latched onto a through ball from Marco Asensio before drilling the ball past Romero - and then getting knocked over by a combination of the Spain keeper and defender Fabricio Bustos, which left the former Chelsea man needing treatment to his leg.
Romero also picked up an injury after being caught in the chest by Costa's boot during the collision, and was replaced by Chelsea's Willy Caballero in the 24th minute.
Argentina went close when Giovani Lo Celso played a neat one-two which released Meza into the Spain penalty area, but the Independiente forward stabbed his shot just wide.
Spain doubled their lead after 27 minutes.
Caballero's stray goalkick was intercepted before being quickly fed down the right to Asensio, whose cutback across the penalty area picked out Isco for a cool sidefoot finish.
Argentina reduced the deficit in the 39th minute when Nicolas Otamendi's header from a corner bounced past David de Gea and inside the far post.
At the start of the second half, Costa was replaced by Iago Aspas - and the Celta Vigo forward had a hand in Spain's third in the 52nd minute.
A ball over the top from Andres Iniesta sent Aspas away down the middle.
As Caballero raced out, Aspas went wide to the right, before sliding a pass back to Isco, who rolled in his second.
Spain, having drawn 1-1 with Germany in Dusseldorf on Friday, soon added a fourth through Thiago Alcantara.
Captain Sergio Ramos thought he had scored just after the hour when knocking the ball in at the far post, but English referee Anthony Taylor had already blown for a foul.
Manchester City defender Otamendi saw his header from a free-kick come back off the woodwork, before tempers threatened to boil over.
Aspas then slotted in another in the 74th minute following a long kick up field by goalkeeper De Gea.
Under a minute later, Isco made sure of the match ball and a night to forget for Argentina when scoring a sixth from Aspas' square pass.
Referee Taylor had to restore order following a melee in the closing moments sparked by a rash challenge on Koke from Argentina Cristian Pavon, which on another night could have seen him sent off.