Branch was born in Halifax County, North Carolina, on November 4, 1782, the son of wealthy landowners. Educated as a lawyer, he occupied himself as a planter and civic leader. Branch served in the North Carolina Senate from 1811 to 1817 and was the state's Governor from 1817 to 1820. After further service in the state Senate, he represented North Carolina in the United States Senate from 1823 until 1829 and was a strong supporter of Andrew Jackson.

When Jackson became President, he selected Branch as his Secretary of the Navy. In that post, Branch promoted several reforms in the Navy's policies and administration, many of which were not implemented until years later. He reduced the resources going to the construction of new ships, while increasing those applied to keeping existing vessels in good repair. Branch also sent the frigate Potomac to the Far East to punish the murderers of a U.S. merchant ship's crew and to generally promote and protect American commerce in the region.

John Branch resigned as Secretary in 1831, during the Petticoat Affair scandal. He was elected in that year to the U.S. House of Representatives and later to North Carolina state political offices. In the mid-1830s, he moved to Leon County, Florida, where he lived for much of the next decade-and-a-half on his Live Oak Plantation. In 1844, President John Tyler appointed him Florida's territorial governor until the 1845 election of a governor under the state constitution. Branch returned to North Carolina in the early 1850s, remaining there until his death on January 4, 1863.

Branch was an uncle of the Confederate General Lawrence O'Bryan Branch.