After attending Oakwood Seminary in Pougheepise, New York, George A. Barton became a minister in the Religious Society of Friends and continued his education at Haverford College, completing a M.A. in 1885. He taught in Rhode Island from 1884 to 1889 then earned a Ph.D. at Harvard and became a professor of Semitic languages at Bryn Mawr College in 1891.

In 1922 Barton moved to the University of Pennsylvania, where he was professor of Semitic languages and the history of religion. He retired in 1931 and held the title of professor emeritus until his death. He specialised in many subjects, particularly in Semitic languages. His many publications cover a wide range of topics in areas such as biblical studies, religion, and linguistics along with translations of Sumerian cuneiform tablets. He was fascinated by bible archeology and wrote a text book on the subject, published in 1916, along with other publications on similar subjects.

Barton specialised in translations of Sumerian & Akkadiann tablets, seals and cylinders. He notably translated a set of Sumerian tablets recovered in 1896-1898 by The University of Pennsylvania's excavation at Nippur initially labelled as "Miscellaneous Babylonian Inscriptions", containing a new creation myth detailing a location called Kharsag. These were later revised by Samuel Noah Kramer and Christian O'Brien.