Chapultepec was the scene of the last-ditch Mexican resistance in the war between Mexico and the United States (1846–48). U.S. forces under General Winfield Scott, having seized Veracruz on the Gulf of Mexico, advanced on the capital. Scott defeated the Mexicans at the suburban bridgehead of Churubusco on Aug. 20, 1847, and continued toward Mexico City; in his path was the hill of Chapultepec, with approximately 5,000 defenders, including cadets from Mexico's military academy. After heavy artillery bombardment on September 12 failed to force their withdrawal, Scott's forces attacked the next morning. The defenders resisted in fierce hand-to-hand combat before capitulating. Several cadets, known in Mexican history as Los Niños Héroes, were killed, one of them, it is said, by leaping from the castle walls, holding the flag lest it be captured. During the following night, Mexican forces were withdrawn, and Scott entered the city on September 14, thus concluding the significant military operations of the war.

In March 1945 all the countries of the Western Hemisphere, except Argentina, sent representatives to the Chapultepec Conference to discuss hemispheric security. An economic charter for the Americas was adopted, as was the Act of Chapultepec, which pledged the signatory nations to take collective action in the event of aggression from within or outside of the Americas against one of their number.