Mauldin took courses at the Chicago Academy of Fine Arts and, in 1940, entered the United States Army. While in the 45th division, he began drawing cartoons about regular soldiers. Eventually he created two cartoon infantrymen, Willie and Joe, who became synonymous with the average American GI. Mauldin began working for Stars and Stripes, the American soldiers' newspaper, and his cartoons were viewed by soldiers all over Europe during World War II, and also published in the United States. Willie was on the cover of Time Magazine in 1943 and Mauldin was there in 1958.
Army officers who were raised in the peacetime army of spit and polish and obedience to orders without question were offended. General George Patton once summoned Mauldin to his office and threatened to "throw his ass in jail" for "spreading dissent". This after one of Mauldin's cartoons made fun of Patton's demand that all sodiers must be clean-shaven and wear ties at all times, even in combat. But Dwight Eisenhower, the Supreme Commander, told Patton to leave Mauldin alone, because he felt that Mauldin's cartoons gave the soldiers an outlet for their frustrations. He told an interviewer later, "Patton was living in the Dark Ages. Soldiers were peasants to him. I didn't like that attitude."
Mauldin's cartoons made him a hero to the common soldier. They often credited him with helping them to get through the rigors of the war. Mauldin himself served on the front lines, landing at Anzio, and receiving a Purple Heart for being wounded.
In 1945, at the age of 23, Mauldin won the Pulitzer Prize. The first collection of his work, Up Front, was a best-seller. The cartoons are interwoven with an impassioned telling of his observations of war. But Mauldin's attempt to carry Willie and Joe into civilian life was unsuccessful, as documented in his memoir, Back Home in 1947. He abandoned cartooning for a while, writing magazine articles and books, including one on the Korean War. He only drew Willie and Joe twice afterwards, once for the funeral of Omar Bradley and once for the funeral of George C. Marshall, both of them considered "soldiers' generals". (He had wanted to have Willie and Joe be killed on the last day of combat, but Stars and Stripes forbade it.)
In 1958, he returned to cartooning on the editorial pages of the St. Louis Post-Dispatch. The following year, he won a second Pulitzer Prize. In 1962 he moved to the Chicago Sun-Times, where he stayed until his retirement in 1991. He died from complications of Alzheimer's disease.
One of his most famous post-war cartoons appeared in 1963, following the assassination of President John F. Kennedy. The cartoon shows the statue of Abraham Lincoln at the Lincoln Memorial, his head in his hands, crying.