Sources indicate that he was born in Carlisle, England,however he may have been born in or near Workington, England, he emigrated with his parents and siblings to Charles Town, Virginia (now West Virginia), where he opened a medical practice. Tiffin headed westward, along with Thomas Worthington in 1798, settling in Chillicothe, Ohio.

He arrived with a letter addressed to the governor of the Northwest Territory, Arthur St. Clair from George Washington, recommending him for public office. Tiffin served as the Speaker of the Territorial House of Representatives from 1799-1801 and as president of the 1802 Constitutional Convention. Tiffin was the obvious choice for the governorship when Ohio was admitted to the Union the next year. He was elected almost without opposition to a first term and re-elected by similarly overwhelming numbers two years later.

Tiffin was elected to the U.S. Senate in 1806 and resigned in March 1807 to take his seat. He served only two years, however, resigning after the death of his wife. He spent only a few months at home, however, before being elected to the Ohio House of Representatives, where he served as speaker from 1809-1811. Tiffin became the first commissioner of the General Land Office, which managed the land allocations of federal land.

He quickly helped remove the federal records from Washington before it was sacked during the War of 1812. In 1814, he became the Surveyor General of the Northwest Territory, exchanging positions with Josiah Meigs so that he might spend more time near his home in Chillicothe. Tiffin served in the post until a few weeks before his death. The city of Tiffin in NW Ohio is named after him.