In 1858, Rule and his brother, James, opened a general store at the corner of State Street and Cumberland Avenue in Knoxville.

By 1860, this store had closed, and William joined the staff of Brownlow's Knoxville Whig, a radical and controversial pro-Union newspaper.

On November 10, 1861, in the early days of the Civil War, Rule eluded Knoxville's Confederate occupiers to carry news and messages to Brownlow, who was hiding out in Wears Valley.

That year many towns in the Mississippi Valley and related tributaries suffered high mortality in a cholera epidemic, associated with contaminated water.

Rule spearheaded a successful initiative to establish a city waterworks, which Knoxville voters approved in June of that year.

That evening, James W. Wallace, editor of the Tribune, angrily accosted Rule on Gay Street, and demanded he issue a retraction.

During the same period, Rule spoke out against Appalachian stereotypes (which were beginning to take shape), arguing that people from the region had normal levels of intelligence, but suffered due to Southern states' lack of funding for public schools.

After the Journal published an article questioning the competence of Dr. A. T. West, who had been appointed city physician by the Board of Aldermen, West's sons, John and William, confronted Rule's brother, James (an editor for the Journal), outside St. John's Episcopal Church, and demanded he reveal the article's author.

Rule was shot through the wrist and stabbed before he managed to draw a pistol and fire blindly, killing John West.