After spending a decade in the state legislature, Slaughter was elected the fourth Lieutenant Governor, serving under Charles Scott.

He sought to be sworn in as governor, but public sentiment turned against him when he replaced Shelby's son-in-law with John Pope as Secretary of State.

Pope was an unpopular figure in Kentucky and, after his appointment, some in the General Assembly began to call for a special election to replace Slaughter.

Following his term as governor, Slaughter became a Baptist lay minister and served on the first board of trustees of Georgetown College.

[3] He became known for his generosity, and his large mansion on the turnpike to Lexington was nicknamed "Wayfarer's Rest" because of the vast number of travelers that he allowed to stay there.

[13] Despite Shelby's immense popularity, Slaughter refused to withdraw from the race and was soundly beaten by more than a two-to-one margin.

[13] Following his defeat, Slaughter took a two-year hiatus from public life, and engaged in farming at his estate in Mercer County.

[6] In 1814, he answered Governor Shelby's call for volunteers to serve in the army of the Southwest under General Andrew Jackson.

[14] When the Quartermaster general did not deliver promised supplies to Slaughter's regiment, private funds had to be used to purchase boats for their travel down the Mississippi River.

This was the first time a sitting governor had died in office in Kentucky, and some questioned the legality of Slaughter's status in the position.

[2] Following Governor Madison's death, Secretary of State Charles Stewart Todd offered to step down if Slaughter preferred to appoint someone else to the post.

[20] The letter was not an explicit resignation, as Todd emphatically declared his intention to work with Slaughter should the governor choose to retain him.

[2] The move was panned in the state's newspapers, and by prominent citizens such as future governor James Turner Morehead.

Yet Slaughter followed up with another unpopular decision, appointing Martin D. Hardin, a member of the hated Federalist Party, to fill the Senate seat of William T. Barry.

The Kentucky House passed a bill calling for such elections by a vote of 56–30, but the measure died in the state senate.

[2] The General Assembly censured both Slaughter and Pope for failing to require the proper security and oath of office for the state treasurer.

He suggested a comprehensive system of public schools and, though the idea had been proposed by previous governors, Slaughter devised a means of funding it.

The hostile legislature refused the plan and overrode Slaughter's vetoes of bills that allowed individual schools to be supported by lotteries.

Slaughter further proposed a reform of the penal system and recommended internal improvements, including the creation of a state library.

[13] Slaughter's governorship was further complicated by the financial panic of 1819, and he spent the majority of his term working to stabilize that state's economy.

[12] Following his term in the state House, Slaughter retired from politics and became an active lay minister of the Baptist faith.