His uncle and namesake, John Randolph Grymes, was a loyalist during the American Revolution who joined the British Army under the former Royal Governor of Virginia Lord Dunmore.

[1] On May 4, 1811, Grymes was appointed to replace his deceased brother Philip as the U.S. attorney for Louisiana district,[9] serving until December 1814, when he resigned his post to represent the pirate Jean Lafitte.

[10] During the War of 1812, Grymes was part of General Andrew Jackson staff as an aide-de-camp during the Battle of New Orleans.

[12] As an attorney, he was law partners with Edward Livingston and was one of Jackson's lawyers in the case over the Second Bank of the United States,[6] he opposed Daniel Webster in court against Myra Clark Gaines,[6] and, reportedly, he earned $100,000 in the batture (or alluvial) land case against Edward Livingston.

[33] Through his daughter Athenais, he was a grandfather of Medora von Hoffmann (1856–1921), who married Marquis de Mores, a French-born nobleman who was a frontier ranchman in the Badlands of Dakota Territory; he was assassinated in Algeria in 1896.

[34] He was also the grandfather of Pauline Grymes (1858–1950), who married the wealthy German industrialist Baron Ferdinand von Stumm whose family owned the Neunkirchen Iron and Steelworks[6] in St. Petersburg, Russia in 1878.