John Selby Spence (February 29, 1788 – October 24, 1840) was an American politician.
Born near Snow Hill, Maryland, Spence attended the common schools and graduated from the medical department of the University of Pennsylvania at Philadelphia in 1809 and practiced in Worcester County, Maryland.
Spence served as a member of both the Maryland House of Delegates and as a member of the Maryland State Senate.
In 1836, Spence was elected as an Anti-Jacksonian (later Whig) to the United States Senate to fill the vacancy caused by the death of Robert H. Goldsborough.
He was reelected in 1837, and served from December 31, 1836, until his death near Berlin, Maryland, in 1840.