Isco netted a hat-trick for the 2010 world champions, while Diego Costa, Thiago and Iago Aspas were also on the scoresheet against an Argentina team that were once again without the services of Lionel Messi.
Spain boss Julen Lopetegui made two changes to the team that started the 1-1 draw with Germany on Friday night - Marco Asensio coming in for David Silva, while Costa replaced Rodrigo at centre-forward.
As for Argentina, Messi was again absent for the international friendly through injury, but there were spots for the likes of Javier Mascherano and Gonzalo Higuain, while Independiente midfielder Maximiliano Meza made his international debut.
Argentina had the first opportunity of the match in the eighth minute when Meza picked out Higuain with a brilliant cross from the left, but the Juventus striker somehow bundled the ball over the crossbar from close range.
It was Spain that took the lead in the 12th minute, however, when Asensio's cute pass released Costa, and the Atletico Madrid forward managed to convert past the onrushing Sergio Romero.
Argentina's next chance arrived in the 25th minute when Meza broke into the Spain box, but the number 27 was denied by a fine last-ditch challenge by Sergio Ramos, who was making his 150th appearance for his country.
Spain doubled their lead in the 27th minute when Asensio worked some space in a wide position before picking out Isco, who placed the ball into the back of the net with a calm finish.
Argentina were back in the match in the closing moments of the first half, however, when a header from Nicolas Otamendi bounced past Spain stopper David de Gea, who might feel that he should have done better.
Spain restored their two-goal advantage in the 52nd minute though, with Isco carefully placing the ball into the bottom corner following smart work from Aspas in a wide position.
La Roja then had their fourth in the 55th minute when Thiago swept the ball into the corner of the net following a clever touch from Aspas, who had met a cross from the brilliant Isco.
Ramos thought that he had scored a fifth for Spain just past the hour, but the referee's whistle denied the centre-back. Otamendi then headed against the Spain post in the 67th minute as chances continued to arrive in Madrid.
The home side had their fifth in the 74th minute when Aspas raced onto a long ball before converting, and it was 6-1 less than one minute later when Isco smashed the ball into the bottom corner for his third of the night following more hopeless defending from the South American nation.
Messi was seen vacating his seat shortly after Spain's sixth goal went in, and the latter stages were marred by a number of late challenges as English referee Anthony Taylor was forced to stop play on a number of occasions.
SPAIN (4-3-3): De Gea; Carvajal, Pique (Azpilicueta 72'), Ramos, Alba (Alonso 79'); Thiago (Parejo 82'), Koke, Iniesta (Saul 56'); Asensio, Costa (Aspas 46'), Isco (Vazquez 76')
ARGENTINA (4-5-1): Romero (Caballero 22'); Bustos (Mercado 62'), Otamendi, Rojo, Tagliafico; Biglia, Mascherano (Pavon 56'), Banega (Perez 62'), Lo Celso (Acuna 84'), Meza; Higuain (Martinez 59')