After the battles of Monterrey and Buena Vista, much of Zachary Taylor's Army of Occupation was transferred to the command of Major General Winfield Scott in support of the upcoming campaign. Polk had decided that the way to bring the war to an end was to invade the Mexican heartland from the coast. Mexican military intelligence knew in advance of U.S. plans to attack Veracruz, but internal government turmoil left them powerless to send crucial reinforcements before the American assault commenced. On March 9, 1847, Scott performed the first major amphibious landing in U.S. history in preparation for a siege. A group of 12,000 volunteer and regular soldiers successfully offloaded supplies, weapons, and horses near the walled city using specially designed landing crafts. Included in the invading force were several future generals: Robert E. Lee, George Meade, Ulysses S. Grant, James Longstreet, and Thomas "Stonewall" Jackson.

Veracruz was defended by Mexican General Juan Morales with 3,400 men. Mortars and naval guns under Commodore Matthew C. Perry were used to reduce the city walls and harass defenders. The bombardment on March 24, 1847, opened in the walls of Veracruz a thirty-foot gap. The defenders in the city replied with their own artillery, but the extended barrage broke the will of the Mexicans, who faced a numerically superior force, and they surrendered the city after 12 days under siege. U.S. troops suffered 80 casualties, while the Mexicans had around 180 killed and wounded, with hundreds of civilians killed. During the siege, the U.S. soldiers began to fall victim to yellow fever.