He was the author of many learned works. He became a Dissenting academic and author, and was the first Fellow of the Royal Society from a Nonconformist background. He was also elected a Fellow of the Geological Society at a time when there was considerable debate about accepting the idea of geological time, and if so to find ways of reconciling this with the teachings of the Old Testament.
Throughout his life he worked for the abolition of slavery.
A committee of Nonconformist merchants and ministers, including Pye-Smith, founded Mill Hill School. for boys on 25 January 1807. Pye-Smith was the theological tutor at the Dissenting academy known as Homerton College near Hackney, London for forty-five years between 1805 and 1850.
His pupils included Robert Halley, future Principal of New College, London. Samuel Dyer, the missionary.
And William Johnson Fox of the South Place Chapel, later the South Place Ethical Society.
Pye-Smith was minister of the Old Gravel Pit Chapel in Chatham Place, Hackney for nearly as long, from 1811-1850. Doctor John Pye Smith died in Hackney in 1851 and is buried below a marble chest tomb monument in Doctor Watts" Walk, at the Congregationalists" non-denominational garden cemetery in the grounds of Abney Park, Stoke Newington, north London. He was the grandfather of Philip Henry Pye-Smith.