William Henry Puthuff was born in 1768 or 1769 and is believed to be a native of Albemarle County, Virginia. He moved to Ohio at some point and served in the Ohio House of Representatives from 1806 to 1807, representing Washington, Gallia, Muskingum, and Athens counties alongside Levi Barber and Lewis Cass. He was serving as the clerk of the Ohio Supreme Court when, at the outbreak of the War of 1812, he enlisted as a volunteer in General William Hull's army at the age of 43. He was made a captain in the 26th Infantry Regiment on May 20, 1813, and in February 1814, was promoted to major in the 2nd Regiment of Riflemen.

By the end of the war, Puthuff was the military commander at Detroit, and took a strict approach to upholding order. In one March 1815 incident, he evicted the wife and children of a resident named Daniel Ames—who was away at the time—as provided for by military law as punishment for Ames illicitly providing whiskey to troops under Puthuff's command. He arrested Ames himself when he came to protest the eviction; Ames sued, and a court later fined Puthuff US$570 (equivalent to $10,555 in 2020), finding he overstepped his authority since the military rules were no longer in effect at the time.

Indian agency in Michilimackinac

With the return to peacetime, Puthuff was compelled to retire from the army, as there was no longer a position for him. He received an address by the citizens of Detroit expressing thanks for his conduct while in command of the city. Lewis Cass, by then governor of the Territory of Michigan, proposed to Alexander J. Dallas, the acting secretary of war, that a new Indian Agency be opened at Michilimackinac. Cass recommended Puthuff for the post, noting his meritorious service during the war and expressing sympathy for the fact that he could not return to his previous job. Puthuff accepted a temporary assignment on August 18, 1815, since Cass was not sure how long it would take for a permanent posting to be approved. He arrived there in late August and was confirmed permanently in December.

After his ouster as Indian agent, Puthuff ran a store in Michilimackinac. He served as president of the village from 1817 to 1821 and again in 1823, and was chief justice of the county court in 1818. Puthuff was appointed as a trustee of the University of Michigan in 1821. He was one of the top 18 vote-earners in a general election held in 1823 to choose nominees for the new Michigan Territorial Council, which was set to replace the previous system where legislative duties were carried out by the governor and judges of the Territory of Michigan. The 18 names were sent to President Monroe, who selected Puthuff as one of the nine members of the council.

The inaugural session of the First Michigan Territorial Council began in Detroit on June 7, 1824, with Puthuff present. He died while the council was still in session, around 9 a.m. on July 17, 1824. The council recommended as his replacement Joseph Miller, who was nominated by Monroe on December 16 and confirmed by the Senate on December 21.