Santa Anna allowed Scott's army to march inland, counting on yellow fever and other tropical diseases to take their toll before Santa Anna chose a place to engage the enemy. Mexico had used this tactic before, including when Spain attempted to reconquer Mexico in 1829. Disease could be a decisive factor in the war. Santa Anna was from Veracruz, so he was on his home territory, knew the terrain, and had a network of allies. He could draw on local resources to feed his hungry army and gain intelligence on the enemy's movements. From his experience in the northern battles on open terrain, Santa Anna sought to negate the U.S. Army's primary advantage, its use of artillery.

Santa Anna chose Cerro Gordo as the place to engage the U.S. troops, calculating the terrain would offer the maximum advantage for the Mexican forces. Scott marched westward on April 2, 1847, toward Mexico City with 8,500 initially healthy troops, while Santa Anna set up a defensive position in a canyon around the main road and prepared fortifications. Santa Anna had entrenched with what the U.S. Army believed were 12,000 troops but in fact was around 9,000. He had artillery trained on the road where he expected Scott to appear. However, Scott had sent 2,600 mounted dragoons ahead, and they reached the pass on April 12. The Mexican artillery prematurely fired on them and therefore revealed their positions, beginning the skirmish.

Instead of taking the main road, Scott's troops trekked through the rough terrain to the north, setting up his artillery on the high ground and quietly flanking the Mexicans. Although by then aware of the positions of U.S. troops, Santa Anna and his troops were unprepared for the onslaught that followed. In the battle fought on April 18, the Mexican army was routed. The U.S. Army suffered 400 casualties, while the Mexicans suffered over 1,000 casualties with 3,000 taken prisoner. The U.S. Army had expected a quick collapse of the Mexican forces. Santa Anna, however, was determined to fight to the end, and Mexican soldiers continued to regroup after battles to fight yet again.