As a child, Frank developed an interest in his late father's sizable library, particularly in the works of his favorite author William Shakespeare. Census records show that Frank attended school throughout his childhood, and he reportedly wanted to become a teacher.
The State Guard's first major engagement was the Battle of Wilson's Creek on August 10, 1861. The state troops fought under Major General Sterling Price alongside the Confederate troops of Brigadier General Ben McCulloch. They numbered in all about 12,000 men. Opposing them was the Army of the West under Union Brigadier General Nathaniel Lyon, totalling 5,400 men. Lyon was killed leading a charge, and his army, under Major General Samuel D. Sturgis, then retreated to Springfield, Missouri. The battle cost the Confederates 1,095 men and the Union 1,235 men, and allowed the victorious Confederates to advance farther north.
On September 13, 1861, Sterling Price's State Guard, including Frank James, besieged Lexington, Missouri, garrisoned by 3,500 men of the Union army, under Colonel James A. Mulligan. On September 20, Price's men finally attacked, and by the early afternoon Mulligan and his men had surrendered. The Confederates had lost 100 men, while the Union forces' losses were estimated at 1,774 men. The Battle of Lexington was the second major victory for the State Guard, and the Confederates gained control of southwestern Missouri by October.
Frank James fell ill and was left behind when the Confederate forces later retreated. He surrendered to Union forces, was paroled and was allowed to return home. However, he was arrested by the local pro-Union militia and not released until he signed an oath of allegiance to the Union.
A bitter guerrilla conflict was soon being waged across the state between bands of Confederate irregulars (commonly known as bushwhackers) and the Federal forces. By early 1863, Frank had joined a guerrilla band led by a former saddler named Fernando Scott. Before long he had switched to the infamous William Clarke Quantrill, attacking both the Union forces and their civilian Union supporters in western Missouri.
The warfare was savage, with atrocities committed by both sides. Militiamen searching for Frank and Fernando Scott's band, for example, raided the Samuel farm and briefly (but not fatally) hanged Dr. Reuben Samuel, Frank's stepfather, torturing him to reveal the location of the guerrillas. Shortly afterward, Frank joined Quantrill's band in the August 21, 1863, Lawrence Massacre.
During his years as a bandit, Frank was involved in at least four shootouts between 1868 and 1876, resulting in the deaths of four bank employees or citizens. The most famous incident was the disastrous Northfield, Minnesota raid on September 7, 1876, that ended with the death or capture of most of the gang.
Aaron Mittenthal, the future grandparent of composer Aaron Copland, who would go on to romanticize the life of the contemporary outlaw Billy the Kid in his 1938 ballet, hired Frank James to work at a Dallas wholesale and retail dry-goods store. It was James's running off with the store's profits that convinced the Mittenthals to leave Texas and return to New York City.
Five months after the murder of his brother Jesse in 1882, Frank boarded a train to Jefferson City, Missouri, where he had an appointment with the governor in the state capitol. Placing his holster in Governor Crittenden's hands, he explained,
Accounts say that Frank surrendered with the understanding that he would not be extradited to Northfield, Minnesota
Frank was tried for only two of the robberies/murders – one in Gallatin, Missouri for the July 15, 1881 robbery of the Rock Island Line train at Winston, Missouri, in which the train engineer and a passenger were killed, and the other in Huntsville, Alabama for the March 11, 1881 robbery of a United States Army Corps of Engineers payroll at Muscle Shoals, Alabama. Missouri General Joe Shelby testified on James' behalf in the Missouri trial. The court was overwhelmed as the two old Confederate veterans embraced. No Missouri jury would have sentenced James after that demonstration. He was acquitted in Alabama as well. Afterwards, Missouri accepted legal jurisdiction over him for other charges but they never came to trial. The Missouri political establishment also kept him from being extradited to Minnesota to be tried in connection with the Northfield Raid.
In the last thirty years of his life, James worked a variety of jobs, including as a shoe salesman and then as a theater guard in St. Louis. One of the theater's spins to attract patrons was their use of the phrase "Come get your ticket punched by the legendary Frank James." He also served as an AT&T telegraph operator in St. Joseph, Missouri. With his old comrade Cole Younger, James took up the lecture circuit. In 1902, former Missourian Sam Hildreth, a leading thoroughbred horse trainer and owner, hired James as the betting commissioner at the Fair Grounds Race Track in New Orleans.