He began his military career at the age of 17, when he was commissioned Second Lieutenant in the U.S. First Infantry, 13 Feb. 1818. His older brother Benjamin F. Harney was already an Army surgeon, and General Andrew Jackson was a family friend and neighbor of the Harneys.

William S. Harney's first assignment was to chase the pirate, Jean Lafitte, out of the Gulf area, forcing Lafitte to move his pirate operations to the Spanish Main. Then William was sent to Florida during the 1st Seminole War. This began his long career working towards peace with the Indians. While the popular idea of the day was to remove and eliminate the Indian populations,  Harney proposed the idea to avoid Indian wars by pursuing a good neighbor policy. He held challenge foot races with the Indians outside the log walls of the fort. His long strides impressed his Crow competitors who he continued to outrun. The Crow awarded him with an Indian name "Man-who-runs-like-the-Deer."   Throughtout his career, Harney worked to improve the nation's treatment of the Indians.

William S. Harney's exploits include chasing General Santa Anna in the Mexican War, fighting the Sauk chief Black Hawk with Col. Zachary Taylor, Captain Abe Lincoln, and Lieut. Jefferson Davis, and working with the Jesuit missionary Father DeSmet, in the northwest.   He led a precedent-setting expedition against the Sioux Indians on the Great Plains in 1855; commanded American troops in Bleeding Kansas in 1857; and commanded the Utah Expedition against the Mormons in 1857-58.   In 1860 and 1861 he was in command of the Department of Oregon and the Department of the West.  And from the standpoint of the Indians was the key figure in the Indian Peace Commission that negotiated treaties with all the Plains Indian tribes in 1867-68.

William S. Harney married Mary Mullanphy, daughter of the Irish philanthropist, John Mullanphy, 17 January 1833. The marriage was not a happy one, and during her husband's campaigns in the West, Mary took their three children to Paris to live. Their two daughter's, Anna and Eliza, married officer's in the French Service, and some references indicate only his son, John Mullanphy Harney, returned to America. Mary (Mullanphy) Harney died in Paris, France, in August 1861, according to her nephew, B.M. Chambers, of St. Louis, Missouri (letter in pension file).

William Selby Harney married Mary E. (Cromwell) St. Cyr on 12 November 1884, in St. Louis, Missouri. Reverend Father Tobyn performed the ceremony, which was held at the cathedral. She was born 24 January 1826, Frederick county, Maryland, the daughter of Richard Cromwell and Caroline Boone. This was the second marriage for both, she being the widow of Paschal Herbert St. Cyr who died in St. Louis, Missouri, 7 June 1871. Mary E. was his housekeeper, and caretaker, and the marriage was protested by his children. Mary E., not only cared for the General in his old age, she entertained his friends and dignitaries, and conducted his business. Some of the letters she wrote in his behalf, still exist (HU12). At his death, 9 May 1889, she was left with only a life estate in the property held by the General, as his large properties and the income so enjoyed by him came mostly from the estate of his former wife, and descended to her heirs. By Special Act of Congress, 29 August 1890, Bill 579, Mary (Cromwell) St. Cyr Harney's name was added to the pension rolls. She died 22 October 1907 (Dept. of Interior letter).

At the start of the Civil War, in 1861, some of William's old comrades of the Indian and Mexican Wars became political leaders. In February, Abe Lincoln became the new President of the U.S., and four days later, Jefferson Davis was elected President of the Southern Confederacy. William Harney was then the Commander of the Department of the West in St. Louis, Missouri.

In April 1861, he was ordered to report to Washington by Lincoln's new Secretary of War, Simon Cameron. The train on which he was traveling was stopped at Harper's Ferry, and a young confederate office boarded announcing "General Harney, sir, you are my prisoner!" He was told a Confederate battalion had surrounded the train, sent with orders to intercept him before he reached Washington. In this way, William S. Harney became the first prisoner taken by the South in the Civil War. Later, in Virginia, William received apologies for the manner in which he was brought there, and he was offered a Confederate command under Robert E. Lee. He had previously served with Lee in the U.S. Army in the Mexican War. William refused, and he was allowed to continue on his trip to Washington.

Harney, who has been described as "politically naive" was engulfed in a rush of political events.  Arriving in Washington, he was shocked to discover he was being relieved of his command. This was a political maneuver of the powerful Blair family, who wanted their own man as Commander of the Department of the West. Even General Winfield Scott, who had many confrontations with William Harney over the years, respected his ability to make peace with the Indians. Scott predicted that this political move by the Blair family would cost the government 100,000 lives and $100 million dollars in military equipment. Later President Lincoln was to agree, when he told Montgomery Blair, "The removal of General Harney was one of the greatest mistakes of my administration."

William S. Harney retired from service 1 August 1863, and he was made Brevet Major General, 13 March 1865, for long and faithful service. He died 9 May 1889, in Orlando, Florida. He was well-liked by many Indian Nations for he tried, although in vain, to have the Indians treated fairly, and consistently urged Congress to honor past treaties with the Indians.  After his retirement, he was recalled to service of his country to work on various Indian Commissions.  After his death the Sioux changed his name from Man-who-runs-like-the-Deer to one of which he would have been very proud, "Man-who-always-kept-his-word".