The annexation of Texas by the United States in 1845 led to the declaration of war against Mexico. Zachary Taylor's victories around Monterrey and the fall of Mexico City brought an end to Mexico's claim to Texas. In the 1848 Treaty of Guadalupe Hidalgo, the Río Grande was declared the boundary, and Mexico received $15,000,000 for 529,019 miles of lost territory. Under this treaty, Laredo became a part of Texas in 1848.

Mirabeau B. Lamar assumed command of the town during the war and denied a petition by Basillio Benavidez, José María González, and José María Ramón, prominent Laredoans, to remain a Mexican Town. Mexicans who wanted to retain their citizenship moved accross the river. This area, previously settled as part of Laredo, became the town of Nuevo Laredo in 1848.

During the Civil War, Laredo was a transfer point on the Confederate cotton route to Mexico. On March 18, 1864, Major Alfred Holt led a union army of about 200 men from Brownsville to destroy 5,000 bails of cotton stacked at San Agustín Plaza. Colonel Santos Benavides rose from his sick bed and, with 42 men, repelled three union charges at Zacate Creek. This became known as the Battle of Laredo.

Camp Crawford, one of a line of U.S. forts along the Río Grande, was established March 3, 1849. It was renamed Ft. McIntosh after Lt.Colonel James S. McIntosh, who perished in the Mexican War at the battle of Molino del Rey. The fort provided protection from the the Indians and the defiant Mexican Juan Cortina. Abandoned during the Civil War, it was reoccupied later and operated untill 1946.

The tumultuous Mexican Revolution of 1910-1920 brought a flood of immigrants to Laredo. In 1914, the carranzista army attacked Nuevo Laredo and sections of the city were burned. Ft. McIntosh was reinforced with 10,000 National Guard soldiers for World War I.