The significance of the Mexican-American War in U.S. history was profound as it led to significant territorial expansion and the fulfillment of Manifest Destiny. The war, which lasted from 1846 to 1848, resulted in the U.S. acquiring vast territories, including present-day California, Arizona, New Mexico, Nevada, Utah, and parts of Colorado and Wyoming through the Treaty of Guadalupe Hidalgo. This expansion intensified the debate over slavery's extension into new territories, contributing to growing sectional tensions and ultimately setting the stage for the Civil War.