Originally part of the State Department, the Mint was made an independent agency in 1799. It converted precious metals into standard coin for anyone's account with no seigniorage charge beyond the refining costs. Under the Coinage Act of 1873, the Mint became part of the Department of the Treasury. It was placed under the auspices of the Treasurer of the United States in 1981. Legal tender coins of today are minted solely for the Treasury's account.

The first Director of the United States Mint was renowned scientist David Rittenhouse from 1792 to 1795. The position was held most recently by Edmund C. Moy until his resignation effective January 9, 2011. (The position is currently vacant, the Mint being run by the Principal Deputy Director, Rhett Jeppson, who was appointed in January 2015).Henry Voigt was the first Superintendent and Chief Coiner, and is credited with some of the first U.S. coin designs. Another important position at the Mint is that of Chief Engraver, which has been held by such men as Frank Gasparro, William Barber, Charles E. Barber, James B. Longacre, and Christian Gobrecht.

The Mint has operated several branch facilities throughout the United States since the Philadelphia Mint opened in 1792, in a building known as "Ye Olde Mint". With the opening of branch mints came the need for mint marks, an identifying feature on the coin to show its facility of origin. The first of these branch mints were the Charlotte, North Carolina (1838–1861), Dahlonega, Georgia (1838–1861), and New Orleans, Louisiana (1838–1909) branches. Both the Charlotte (C mint mark) and Dahlonega (D mint mark) Mints were opened to facilitate the conversion of local gold deposits into coinage, and minted only gold coins. The Civil War closed both these facilities permanently. The New Orleans Mint (O mint mark) closed at the beginning of the Civil War (1861) and did not re-open until the end of Reconstruction in 1879. During its two stints as a minting facility, it produced both gold and silver coinage in eleven different denominations, though only ten denominations were ever minted there at one time (in 1851 silver three-cent pieces, half dimes, dimes, quarters, half dollars, and gold dollars, Quarter Eagles, half eagles, eagles, and double eagles).

A new branch facility was opened in Carson City, Nevada, in 1870; it operated until 1893, with a three-year hiatus from 1886 to 1888. Like the Charlotte and Dahlonega branches, the Carson City Mint (CC mint mark) was opened to take advantage of local precious metal deposits, in this case, a large vein of silver. Though gold coins were also produced there, no base metal coins were.

In 1911 the Mint had a female acting director, Margaret Kelly, at that point the highest paid woman on the government's payroll. She stated that women were paid equally within the bureau.

A branch of the U.S. mint (Manila Mint) was established in 1920 in Manila in the Philippines, which was then a U.S. colony. To date, the Manila Mint is the only U.S. mint established outside the continental U.S. and was responsible for producing coins for the colony (one, five, ten, twenty and fifty centavo denominations). This branch was in production from 1920 to 1922, and then again from 1925 through 1941. Coins struck by this mint bear either the M mintmark (for Manila) or none at all, similar to the Philadelphia mint at the time.

A branch mint in The Dalles, Oregon, was commissioned in 1864. Construction was halted in 1870, and the facility never produced any coins, although the building still stands.