By early 1862, Union troops in the Western theater were building an overwhelming numerical superiority over Southern forces. In April, the Confederacy's Western commander, General Albert Sidney Johnston, saw an opportunity to defeat General Ulysses S. Grant's army at Shiloh, Tennessee. A devastating surprise attack could trap and destroy Grant's forces before General Don Carlos Buell's Federals could link up with them. "Bloody Shiloh" would be the greatest battle fought in the West during the Civil War, a field of strategic importance and savagely determined fighting.

Together with other units of Johnston's Army of the Mississippi, the 1st Florida Infantry Battalion marched northward for four days to reach Shiloh, slowed by rain and mud-clotted roads. Their brigade commander was one of their own, the hard-fighting Patton Anderson, who had been promoted to brigadier general after effectively leading the 1st Florida in its first taste of battle.
Anderson led his troops forward through artillery barrages, waving his hat at Union positions to urge them on. Sustaining heavy casualties, including battalion commander Major Thaddeus A. McDonell, the 1st Florida pressed on. By mid-moming, they had broken through General William Tecumseh Sherman's collapsing line and helped force a Union withdrawal to a new line of defense behind Sherman's headquarters. Their colors followed Anderson and their new battalion commander, Captain W.G. Poole, into every fray.
At 4 pm, Poole's men rallied for the brigade's assault on the Hornet's Nest, the Union stronghold that had repelled about a dozen Confederate attacks. The brigade rushed forward with two more Southern brigades joining the assault. Finally, the Union defenders fell back "to prevent annihilation" (in their commander's words) and Anderson's troops held the Hornet's Nest, one of the Confederacy's finest moments at Shiloh.

he 1st Florida Infantry Regiment (later, a Battalion) was organized in the spring of 1861. It was formed with 10 company commanders, including Captain James Patton Anderson of Jefferson County. A former physician and legislator who had served as a Mexican War volunteer, Anderson was elected commander of the 1st Florida with the rank of full colonel. His first deputies were Lieutenant-Colonel William H. Beard of Tallahassee and Major Thaddeus A. McDonell of Gainsville.
Anderson was a strict disciplinarian who was nonetheless loved and revered by his troops for his bravery under fire and aggressive leadership. After a number of U.S. military forts in Florida were peacefully surrendered to the Confederacy, Anderson first led the 1st Florida into battle on Santa Rosa Island off the coast of Florida, against the New York 6th Infantry and battery units.

Even before its heavy losses at Shiloh, the 1st Florida Infantry Regiment was reduced to battalion size through staffing of other regiments. The 1st Florida was assigned to General Albert Sidney Johnston's Army of the Mississippi, serving at Shiloh under newly promoted Brigadier General Anderson's 2nd Brigade, in General Ruggle's 1st Division, under General Bragg's 2nd Army Corps. The 1st Florida's new commander, Major Thaddeus A. McDonell, was wounded at Shiloh and replaced by Captain W.G. Poole. Poole was cited by Anderson for his gallant leadership throughout the two-day battle.
After the 1st Florida's hard-won triumphs on the first day at Shiloh, the exhausted troops were periodically bombarded through the night by Union gunboats. Overwhelming Union reinforcements provoked a withdrawal of Southern forces on the second day. Grant controlled the battlefield, although heavy Union losses brought him under severe criticism. General P.G.T. Beauregard (who took over the army's command after General Johnston was mortally wounded) also claimed victory, saying that "untoward events saved the enemy from annihilation." Hard-charging Southern units like the 1st Florida had captured over 25 Union flags and standards at Shiloh. 
Later in 1862, the 1st Florida (now part of a regiment including the 3rd Florida) again fought with distinction in Tennessee at Murfreesboro. In May, 1863, the 1st Florida saw action around the siege of Vicksburg, then later in the year saw heavy fighting at Missionary Ridge near Chattanooga and at Chickamauga, where its casualties numbered over 30 percent. In 1864 the remnants of its brigade were combined into the 1st Florida Regiment, which ended the war in the Carolinas.