Charles MacArthur was the second youngest of seven children born to stern evangelist William Telfer MacArthur and Georgiana Welsted MacArthur. He early developed a passion for reading. Declining to follow his father into ministry, he moved to the Midwest and soon became a successful reporter in Chicago, working for the Chicago Tribune and Chicago Daily News. He also wrote several short stories at that time, two of which, "Hang It All" (1921) and "Rope" (1923), were published in H.L. Mencken’s The Smart Set magazine. Eventually he settled in New York City, where he turned to playwriting.
His second marriage was to the stage and screen actress, Helen Hayes, from 1928 until his death. They lived in Nyack, New York. They were preceded in death by their daughter, Mary, who died unexpectedly of polio in 1949 at the age of 19. The shock of her death hastened MacArthur's own, according to those who knew him.