The Barcelona star opened the scoring after just nine minutes and further goals from Gonzalo Higuain three minutes later and Carlos Tevez after 34 minutes gave the South Americans a stunning 3-0 lead at half-time.
The second half was a quieter affair with Fernando Llorente pulling one back for the Spaniards after 83 minutes before Sergio Aguero produced the final margin in injury time.
The win was a huge boost for new coach Sergio Batista, who took over from the sacked Diego Maradona after Argentina crashed out of the World Cup losing 4-0 to Argentina in the quarter-finals in South Africa.
Batista has been given until the end of the year to prove himself.
Spain, though, were without goalkeeper Iver Casillas and fielded only one of the back-four defenders who started against the Netherlands in the World Cup final.
That showed early on as Argentina's fast-attacking forwards exposed Spain's lack of cohesion at the back.
Messi struck the first blow with a superb goal in nine minutes after which he kissed his shirt in celebration to the delight of the home fans who have doubted his commitment to the national team.
Three minutes later, it was the turn of Real Madrid striker Higuain to make it 2-0 running on to a long through ball from Manchester City's Tevez.
Argentina's third goal after 34 minutes was gifted by Spanish goalkeeper Pepe Reina, who slipped when kicking clear allowing Tevez to pounce and score.
Spain, in turn, were unlucky with striker David Villa twice hitting the post, after 28 and 41 minutes.
Spanish coach Vincente del Bosque rang the changes at half-time and that worked well as Spain began to control the midfield.
Argentine goalkeeper Sergio Romero saw another shot come back off the woodwork from substitute Santiago Cazorla after 75 minutes and he made a fine save from Pedro Hernandez three minutes later.
But he was well beaten after 84 minutes when substitute Fernando Llorente spun and fired home from close range.
That counter sparked a late flurry of activity from the home side and a fourth goal from Aguero one minute into injury time, heading home a cross from Gabriel Heinze.
Argentina coach Batista said that the emphatic win proved that Argentina had put the crushing loss to Germany behind them.
"We were sent packing from South Africa, but we could just as well have won the World Cup," he said.
"If Spain this evening did not look like the side that won the World Cup, then the way Argentina played had a lot to do with that.
"We played the way we wanted to play."
Del Bosque said that there was no shame for Spain in losing to Argentina.
"We lost with dignity and never gave up trying," he said.
"Argentina were very fast up front, they move well and it was normal that they controlled the game. They hardly left us any room to play in."
