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At the start of the American Civil War, Garfield tried to obtain an officer's commission in the Union Army. At first that didn't look like it was going to happen. Ohio Governor William Dennison, Jr. asked Garfield to travel to Illinois to acquire weapons and to negotiate with the Governors of Illinois and Indiana for the consolidation of troops. In the summer of 1861 Garfield was rewarded for his efforts when he was commissioned a lieutenant colonel in the Union Army and given command of the 42nd Ohio Volunteer Infantry.
General Don Carlos Buell assigned Colonel Garfield the task of driving Confederate forces out of eastern Kentucky in November 1861. Garfield took command of the 18th Brigade for the campaign. The mission was uneventful until Union forces reached Paintsville, Kentucky, on January 6, 1862, where Garfield's cavalry engaged the Confederates at Jenny's Creek. Garfield positioned his troops so as to deceive the enemy into thinking that he was outnumbered. The Confederates, under Brigadier General Humphrey Marshall, withdrew to the forks of Middle Creek, two miles from Prestonsburg, Kentucky, on the road to Virginia. Garfield attacked on January 9, 1862 and at the end of the day's fighting the Confederates withdrew from the field. Garfield did not pursue them. Instead he decided to withdraw to resupply his men. His victory brought him early recognition and he was promoted to the rank of brigadier general on January 11, 1862.
Garfield commanded the 20th Brigade of Ohio under Buell at the Battle of Shiloh, where he led troops in an attempt, delayed by weather, to reinforce Maj Gen. Ulysses S. Grant. While Grant expressed no criticism of Garfield, he was upset with Buell for taking so long to arrive. Garfield then served under General Thomas J. Wood in the Siege of Corinth, where he assisted in the pursuit of Confederates in retreat. The overly cautious Maj. Gen. Henry W. Halleck permitted the escape of Gen. P. G. T. Beauregard and his troops. Garfield was furious with his commander and he developed a prejudice against commanders who were trained at West Point. Garfield argued that the Union should aggressively carry the war to Southern civilians, but his view was not then shared by the Union leadership.
In the summer of 1862, Garfield's health suddenly took a turn for the worse. He suffered from jaundice and experienced significant weight loss. Garfield was forced to return home, where his wife Lucretia nursed him back to health. He returned to duty that autumn and served on the Court-martial of Fitz John Porter. Garfield was then sent to Washington to receive further orders.
In the spring of 1863, Garfield returned to the field as Chief of Staff for William Rosecrans, commander of the Army of the Cumberland. Rosecrans was a highly energetic and intelligent man and he and Garfield became close friends. The two men had endless discussions on many topics including religion. Rosecrans, who had converted from Methodism to Catholicism, succeeded in softening Garfield's view of Catholics. Garfield created an intelligence corps in the Army of the Cumberland and he also recommended that Rosecrans should replace commanders Alexander McCook and Thomas Crittenden. Rosecrans ignored these recommendations, a decision he came to regret in the Battle of Chickamauga. Garfield came up with a plan to trap Confederate General Braxton Bragg in Tullahoma. But Rosecrans stalled his army's move against Bragg and made repeated requests for additional troops and supplies. Garfield argued with his superior for an immediate advance on Bragg's army. Garfield planned a cavalry raid behind Bragg's line, but the raid failed due to poor execution and bad weather. Garfield was able to convince Rosecrans to pursue Bragg's army.
At the Battle of Chickamauga, Rosecrans issued an order which intended to fill a gap in his line, but which actually created one. As a result, his right flank was vulnerable. Rosecrans concluded that the battle was lost and headed for Chattanooga to establish a defensive line. Garfield, however, thought that part of the army had held and, with Rosecrans's approval, he headed across Missionary Ridge to survey the situation. Garfield correct, while Rosecrans' error reinforced critical opinions about his leadership. Rosecrans's army was left in Chattanooga surrounded by Bragg's army. Garfield sent a telegram to Secretary of War Edwin M. Stanton alerting Washington to the need for reinforcements to avoid annihilation. 20,000 troops were sent to Chattanooga by rail within nine days.
When Ulysses Grant's assumed command of the Union Army, he decided to replace Rosecrans with George H. Thomas. Garfield was issued orders to report to Washington, where he was promoted to major general. He was unsure of whether he should return to the field or assume the Ohio congressional seat he had won in October 1862. After a discussion with Lincoln, he decided in favor of the latter and resigned his commission. Historian Jean Edward Smith is of the opinion that Grant did not have confidence in Garfield, since Grant put Thomas in charge of the Army of the Cumberland, rather than Garfield, after Rosecrans was dismissed.
Garfield privately communicated his criticisms of Rosecrans in a confidential letter to his friend, Secretary of the Treasury Salmon P. Chase. According to historian Bruce Catton, Garfield's statements influenced the Lincoln administration to find a replacement for Rosecrans.
In October 1862 Garfield defeated D.B. Woods by a two-to-one margin in the general election for his district's House seat in the 38th Congress. After the election, Garfield was anxious to determine his next military assignment and went to Washington for this purpose. Garfield became a member of the Radical Republicans, led by Salmon P. Chase. Garfield praised the Emancipation Proclamation. He held a negative opinion of General George McClellan, who would be Lincoln's opponent in the 1864 election, though he was said not to be a strong supporter of Lincoln's because he wished the President to be more aggressive on the issue of abolition.
Despite wanting to return to service, Garfield reluctantly took his seat in the House of Representatives, where he rose to a position of prominence.