After living in Philadelphia from 1795 to 1799 where the elder Gales transcribed the debates in Congress and owned the Independent Gazetteer, he moved with his family to Raleigh, North Carolina.

Gales, Jr. was educated at the University of North Carolina at Chapel Hill and in 1807 settled in Washington, D.C., where he became the assistant and partner of Samuel Harrison Smith in the publication of the National Intelligencer.

In 1810 Gales became sole proprietor of the journal and made it a triweekly publication, and in 1813, having previously formed a partnership with his brother-in-law, William Winston Seaton, the paper was issued daily and so continued until 1867 (after the deaths of both publishers).

For many years Gales and Seaton were the official printers to Congress, and the files of the National Intelligencer, containing a running account of the debates in both Houses, are one of the most valuable sources of United States congressional history for more than a quarter of a century.

Increasingly it became a political newspaper, spokesman for the opponents of Jackson and supporters of John Quincy Adams, Henry Clay, and the Whig Party.