Red Tails takes place in 1944, as the 332nd Fighter Group, all of whom are African-American, is sent into battle. The 332nd Fighter Group suffered much racism during their recruitment and into their training, and it is evident as they are given worn-out Curtiss P-40 Warhawks to fly into combat. The group is asked to support the allied landing in Italy, and use this as their opportunity to shine. During the mission, they face combat and register their first victory. Due to their victory, the USAAF bomber command is impressed with them and ask them to become Boeing B-17 Flying Fortress bomber escorts as it is a dangerous job which needs the best. They accept as long as they are given more modern planes, which they are. It is realized that the mistake of previous escort fighters is that they would go after Germans costing them protection for the bombers, so the pilots will now stay with the bombers no matter what. Their first mission is successful, losing not a single bomber. Two pilots are taken down during the mission, one nearly dies and the other is captured.
Though formerly frowned upon due to their race, the Tuskegee Airmen begin to gather respect from white counterparts. The respect is not only being voiced vocally, but they are even allowed into "whites only" clubs and events. The pilot who was captured during their first mission is sent to a POW camp, which he and other POWs attempt to escape. The escape works, but he selflessly sacrifices himself so other POWs can get away. One of the POWs that got away goes to the 332nd's base and tells of his heroics, and they assume he was killed.
The Tuskegee Airmen are now given the job of escorting the first American bombers to Berlin. The 332nd is only needed for the first leg of the mission, but because the squadron suppose to take over for the 332nd for the second part never shows, they decide to go all the way. During the mission, they are attacked by the Germans, and though major underdogs, they are take a few down. The attack doesn't end perfect, however, as one of the airmen is killed protecting another.
In the end, at the funeral of the fallen airmen, a former pilot is reconnected with the fighters. The pilot taken as a POW arrives at the funeral, and though previously assumed dead, is somehow alive and reunited with the 332nd! Eventually, the airmen are awarded Presidential Unit Citation to honor their amazing accomplishments!