John Middleton Clayton (October 13, 1840 – January 29, 1889) was an American politician who served as a Republican member of the Arkansas House of Representatives for Jefferson County from 1871 to 1873 and the Arkansas State Senate for Jefferson County. In 1888, he ran for a seat in the United States House of Representatives but lost to Clifton R. Breckinridge. Clayton challenged the results and was assassinated in 1889 during the challenge to the election. He was declared the winner of the election posthumously. The identity of his assassin remains unknown.

He was the brother of Arkansas Governor and U.S. Senator Powell Clayton, President Judge of the Thirty-Second Judicial District of Pennsylvania Thomas J. Clayton and twin-brother to U.S. Attorney W.H.H. Clayton.