William S. Harney's military career was initiated by his brother, Dr. Benjamin F. Harney, then an Army surgeon in Baton Rouge, Louisiana. He asked Andrew Jackson, hero of the War of 1812 and current Commander of the Army of the South, to write a letter to the Secretary of the Navy asking for Harney's acceptance into the Navy. This occurred July 23, 1817. Harney visited his brother and met high ranking military officers. He so impressed them that they arranged a commission for him as US Navy second lieutenant, signed by then President James Monroe. Harney instead chose to serve under Andrew Jackson in the Army. His first military assignment under General Andrew Jackson was in 1818, as a second lieutenant in the 1st U.S. Infantry. He forced the pirate Jean Lafitte to move his operations from the Louisiana territory to the Spanish Main. Harney served with distinction during the Seminole Wars and the Blackhawk War.

During the Mexican - American War, he was appointed colonel and commanded the 2nd Dragoons. They were attached to John E. Wool's command during the Chihuahua Expedition and the Battle of Buena Vista. Harney joined Winfield Scott's Army as senior cavalry officer, where he fought with distinction at the battle of Cerro Gordo, and received a promotion to brevet brigadier general. On May 14, 1849, on the death of Bvt. Major General William J. Worth, Harney assumed command of Military Department Number Five, which comprised almost all of the settled portion of Texas.

While on leave in Paris in 1854, Harney was recalled by the US government to lead a punitive expedition against the Sioux, after they killed a small US Army detachment in Nebraska Territory, an event called the Grattan Massacre. He led attacks against the Sioux culminating in the Battle of Ash Hollow in 1855, in which the Sioux were defeated. After the battle, the Sioux called Harney "Woman Killer." This was one of the opening battles in the more than two decades of the Plains Indian Wars.

Harney was next assigned command of the Department of Oregon. During this time, he sent troops under Captain George E. Pickett to San Juan Island, precipitating the Pig War with British forces. Due to the altercations with the British, he was recalled by the Army. Briefly commanding troops during the Utah War, he was again recalled and placed in command of troops sent to deal with the guerrilla warfare of Bleeding Kansas. Promoted to brigadier general on June 14, 1858, Harney was one of the four general officers in the regular army at the opening of the Civil War.

Harney commanded the Army's Department of the West at Jefferson Barracks in St. Louis, Missouri, in 1861. Missouri Governor Claiborne Jackson was pro-secession, but the majority of Missourians were Unionist. After the bombardment of Fort Sumter, President Lincoln called for troops to suppress the rebellion. Jackson refused, and began plotting with Confederate authorities to bring about Missouri secession by a military coup.

On 10 May 1861, Captain Nathaniel Lyon, commander of the St. Louis Arsenal, led a force of unofficial Unionist "Home Guards" to capture a force of state militia that were poised to seize the Arsenal - acting without any authorization from Harney, his nominal superior. The Camp Jackson Affair resulted in a bloody riot in St. Louis, and Harney was horrified. The state legislature responded by reorganizing the militia as the Missouri State Guard, and authorizing it to resist "invasion" by Federal troops.

Harney tried to calm the situation. He agreed to the Price - Harney Truce with Guard commander Sterling Price, under which he agreed that the State Guard would control most of Missouri, while Federal troops stayed near St. Louis. Missouri Governor Claiborne Jackson (who favored secession) swore allegiance to the Union in the deal.

This was not acceptable to Unionist leaders in Missouri, such as Republican leader Frank Blair, as Price did nothing to prevent the organization of pro-Confederate forces or protect Unionists in his territory. Blair reported all this to the Lincoln administration in Washington, and was authorized to replace Harney with Lyon. Blair acted on 30 May. Harney was called to Washington to discuss the situation. He was captured by Confederates en route and was offered a command by Confederate General Robert E. Lee. He refused and was released to continue on to Washington, where he was permanently relieved of his command.

Harney remained in Washington, serving in various administrative positions. He retired in 1863, and was breveted to Major General in 1865, in recognition of his long and distinguished career.

Though a then well known cavalry officer of the Indian Wars, William Harney worked for peace with the Indians by advocating a good neighbor policy and strove throughout his career to improve the nation's treatment of the native population, vainly seeking to have them treated fairly. The Crows gave him the name "Man - who - runs - like - the - deer" after he challenged them to foot races outside the walls of the fort. After the Civil War he was a key figure in the Indian Peace Commission that negotiated treaties with all the Plains Indians in 1867 - 68, and urged Congress to honor past treaties. After his death in Orlando, Florida, the Sioux changed his name to "Man - who - always - kept - his - word".

Harney was known for having a particularly brutal streak. Harney commanded the US troops at the Battle of Ash Hollow in 1855, which some view as a massacre rather than a battle, and which resulted in the killing of roughly 85 men, women and children. He was also court martialed by the army four times, as well as tried in a civilian court in St. Louis, Missouri, for bludgeoning his female slave Hanna to death for losing his keys — he fled the state when a mob pursued him, he was ultimately found not guilty. In the Mexican - American war, he oversaw the execution of thirty members of the San Patricio Battalion after the Battle of Chapultepec; these were primarily Irish Catholic immigrants who had deserted the US army to fight for Mexico. While overseeing the hangings, Harney ordered Francis O’Conner hanged even though both his legs had been amputated the day before. When the army surgeon informed the colonel that the absent San Patricio had lost both his legs in battle, Harney, in a rage, replied:

This incident was in violation of the articles of war requiring swift executions. He was never punished for his actions and was promoted to brigadier general shortly after, accompanying the commander in chief in a triumphal march in Mexico City. Harney's actions in regards to the hanging of the amputee were not in fact a crime, in that the order to hang the members of the San Patricio brigade as an example did not originate in his command but in higher ups in the command. Harney's statement is very telling in this sense. Harney refers to his "orders" to hang 30 men. The "war crime" here involves the argument that these men should have been executed by firing squad and not by hanging, but this was not Harney's decision.