Politics intrigued Heiskell and he used the columns of the Register to champion both candidate and cause. As a result, he became a close friend and political ally of Andrew Jackson, Henry Clay, and James K. Polk. Although a supporter of Jackson against John Quincy Adams, Heiskell then supported Hugh Lawson White for president rather than Jackson's hand-picked successor, Martin Van Buren, in the 1836 election. Heiskell campaigned relentlessly for White in the editorial columns. When the election was over, White had 39,500 Tennessee votes to Van Buren's 21,500.

Heiskell became a tireless campaigner for public education and civic improvement, with service on countless boards and commissions. He was co-founder and treasurer of the Knoxville Public Library. He served as a trustee of the Knoxville Female Academy and its successor, the East Tennessee Female Institute, from 1827 until his death. He was also a trustee of East Tennessee College, now the University of Tennessee, and served on the Knoxville Board of Mayors and Aldermen from 1825 until 1831 and in 1835 for a brief period as mayor of Knoxville. In 1847, Heiskell was elected to the Tennessee State Senate. In addition to his political activities, Heiskell was the president of the Tennessee Press Association in 1836 and was referred to as the father of Tennessee journalism.

In 1837, Heiskell sold the Register to Col. W. B. A. Ramsey and Robert Craighead. He then moved west of Knoxville to Fruit Hill farm where he lived until 1880. His wife died in 1851, and he married the widowed Alice Gale (Armstrong) Fulkerson two years later. He died on November 29, 1882, in Rogersville, Tenn.