Francois' wife received a last-minute warning and escaped with their two sons, arriving with Pierre Laurent Jumelle at Charleston, and settling in Camden, South Carolina.
On January 11, 1861, at the outbreak of the American Civil War, Villepigue publicly affixed the Great Seal of the State of Florida to Florida's Declaration of Independence on the east portico of the State Capitol, turned to face an assembled crowd, and "in a clear distinct voice proclaimed Florida an independent nation.
Villepigue enlisted in the Confederate States Army on March 3, 1862, at Tallahassee, joined Robert Howard Gamble's Artillery.
In April 1862, he was appointed the first lieutenant of the Leon Light Artillery under Gamble, then a captain.
He served with the Kilcrease Light Artillery until November 22, 1864, when he resigned his commission to become Secretary of the Confederate Senate.