The long-haired Deportivo Coruna player struck in the 52nd minute after being given space out wide by a pinpoint cross from Alberto Medina at the Reliant Stadium.
Guardado unleashed a rasping left-foot strike that was parried away by Angola goalkeeper Joao Mamona Luis Lama but the Mexican followed up and buried the ball in the left side of the net to send the sellout crowd of 70,000 into a frenzy.
Mexico, who play hosts South Africa in the opening game of the World Cup next month, dominated the match with Guardado, Medina and the experienced Cuauhtemoc Blanco prominent in attack.
However, they squandered a string of chances against a team who failed to qualify for the World Cup and were also denied by some superb saves by Lama.
Following their 1-0 win over Senegal on Monday, Mexico at least wrapped up their U.S. tour on a triumphant note and will return home to host fellow World Cup qualifiers Chile on Sunday before they head to South Africa.
Mexico are in Group A at the June 11-July 11 World Cup finals along with the hosts, France and Uruguay.
‘The pure simplicity of the way Slot has managed the squad is probably the biggest thing I could say about him. It’s not broken, so let’s get on with it’: Liverpool legend full of admiration for Jurgen Klopp's successor at Anfield
‘I trained at Spurs and thought they’d give me a chance. But I received a letter thanking me but saying they didn’t think I was good enough – I was gutted’: How Tottenham missed out on signing Wales legend John Toshack
