Eaker drew much of his initial staff, including Captain Frederick W. Castle, Capt. Beirne Lay, Jr., and Lt. Harris Hull, from former civilians rather than career military officers, and the group became known as "Eaker's Amateurs". Eaker's position as commander of the Eighth Air Force led to his becoming the model for General Pat Pritchard in the 1949 movie Twelve O'Clock High.
Throughout the war, Eaker was an advocate for daylight "precision" bombing of military and industrial targets in German-occupied territory and ultimately Germany — of striking at the enemy's ability to wage war while minimizing civilian casualties. The British considered daylight bombing too risky, and wanted the Americans to join them in night raids that would target wider areas, but Eaker persuaded a skeptical Winston Churchill that the American and British approaches complemented each other in a one-page memo that concluded, "If the R.A.F. continues night bombing and we bomb by day, we shall bomb them round the clock and the devil shall get no rest." He personally participated in the first US B-17 Flying Fortress bomber strike against German occupation forces in France, bombing Rouen on August 17, 1942.
Eaker was promoted to lieutenant general in September 1943. However, as American bomber losses mounted from German defensive fighter aircraft attacks on deep penetration missions beyond the range of available fighter cover, Eaker may have lost some of the confidence of USAAF Commanding General Henry Arnold. When General Dwight D. Eisenhower was named Supreme Allied Commander in December, 1943, he proposed to use his existing team of subordinate commanders in key positions, including Lt. Gen. James Doolittle. Doolittle was named Eighth Air Force Commander, and Arnold concurred with the change.
Eaker was re-assigned as Commander-in-Chief of the Mediterranean Allied Air Forces, having under his command the Twelfth and Fifteenth Air Forces and the British Desert and Balkan Air Forces. He did not approve of the plan to bomb Monte Cassino in February 1944, considering it a dubious military target, but ultimately "signed off" and gave in to pressure from ground commanders; historians of the era now generally believe Eaker's skepticism was correct and that the ancient abbey at Monte Cassino could have been preserved without jeopardizing the allied advance through Italy.
On April 30, 1945, General Eaker was named deputy commander of the Army Air Forces and chief of the Air Staff. He retired August 31, 1947, and was promoted to lieutenant general in the United States Air Force on the retired list June 29, 1948.
Almost 30 years after his retirement, Congress passed special legislation awarding four-star status to General Eaker, prompted by Senator Barry Goldwater and endorsed by President Ronald Reagan. On 26 April 1985, Chief of Staff General Charles A. Gabriel and Ruth Eaker, the general's wife, pinned on his fourth star.