At 4:30 p.m. on April 21, scout Deaf Smith (pronounced "Deef Smith") announced the burning of Vince's Bridge, which cut off the only avenue of retreat for both armies without having to cross water more than 10 feet (3.0 m) deep. The main Texan battle line moved forward with their approach screened by the trees and rising ground. Emerging from the woods, the order was given to "advance" and a fifer began playing the popular tune "Will you come to the bower I have shaded for you?" General Houston personally led the infantry, posting the 2nd Volunteer Regiment of Colonel Sidney Sherman on his far left, with Colonel Edward Burleson's 1st Volunteer Regiment next in line. In the center, two small brass (or iron) smoothbore artillery pieces (donated by citizens of Cincinnati, Ohio) known as the "Twin Sisters," were wheeled forward under the command of Major George W. Hockley. They were supported by four companies of infantry under Captain Henry Wax Karnes. Colonel Henry Millard's regiment of Texas regulars made up the right wing. To the extreme far right, 61 Texas cavalrymen under newly promoted Colonel Mirabeau B. Lamar planned to circle into the Mexicans' left flank. Lamar had, the day before, been a private in the cavalry but his daring and resourcefulness in a brief skirmish with the Mexicans on April 20 had led to his immediate promotion to colonel.
The Texan army moved quickly and silently across the high-grass plain, and then, when they were only a few dozen yards away, charged Santa Anna's camp shouting "Remember the Alamo!" and "Remember Goliad!," only stopping a few yards from the Mexicans to open fire. The Texans achieved complete surprise. It was a bold attack in broad daylight but its success can be attributed in good part to Santa Anna's failure to post guards during the army's siesta. Santa Anna's army primarily consisted of professional soldiers, but they were trained to fight in ranks, exchanging volleys with their opponents. The Mexicans were ill-prepared and unarmed at the time of the sudden attack. Most were asleep with their soldaderas (i.e., wives and female soldiers), some were out gathering wood, and the cavalrymen were riding bareback fetching water. General Manuel Fernández Castrillón desperately tried to mount an organized resistance, but was soon shot down and killed. His panicked troops fled, and Santa Anna's defensive line quickly collapsed.
Hundreds of the demoralized and confused Mexican soldiers were routed, with many being driven into the marshes along the river to drown. The Texans chased after the fleeing enemy, shouting "take prisoners like the Meskins do!", in reference to the burning of bodies after the Alamo and the mass murder of Texans at Goliad. Some of the Mexican cavalry plunged into the flooded stream by Vince's bridge but they were shot as they struggled in the water. Houston tried to restrain his men but was ignored. Gen. Juan Almonte, commanding what was left of the organized Mexican resistance, soon formally surrendered his 400 remaining men to Rusk. The rest of Santa Anna's once-proud army had disintegrated into chaos. From the moment of the first charge the battle was a slaughter, "frightful to behold", with most of the Texan casualties coming in the first minutes of battle from the first Mexican volley.
During the short but furious fighting, Houston was shot in the left ankle, two of his horses were shot from under him, and Santa Anna escaped. The combat itself lasted 18 minutes but the slaughter of the Mexicans continued for "another hour or so". The Texan army had won a stunning victory, killing about 700 Mexican soldiers, wounding 208, and taking 730 prisoners while suffering 9 killed and 30 wounded.