He served as minister of Second Presbyterian Church in Charleston, South Carolina for more than 40 years, from 1832 until his death.

[2] He then emigrated with his family to the United States in 1830, and completed his studies at Princeton Theological Seminary, graduating in 1831.

In 1850, Smyth wrote The Unity of the Human Races Proved to be the Doctrine of Scripture, Reason, and Science.

[4][5] Colin Kidd suggests that he was the "most influential defender of monogenesis in the nineteenth-century United States".

[4][5] Barry Waugh notes that "in Charleston, he was thought an Abolitionist, while in Britain, he was seen as a supporter of slavery.

"[2] Smyth was instrumental in the establishment of Zion Presbyterian Church for black people, and for this he was vilified by some Southerners.