Guardado made his first appearance for Mexico in a friendly match against Hungary on 14 December 2005, four months after his first-team debut with Atlas. He was then called up to represent his country at the 2006 FIFA World Cup in Germany, where he appeared in the round of 16 1–2 loss to Argentina, starting as a shifting attacking midfielder/wing-back alongside Ramón Morales but was replaced by Gonzalo Pineda after picking up an injury in the second half; after the departure of manager Ricardo La Volpe, his replacement Hugo Sánchez kept the player in his squad.