When Red Skelton was drafted in March 1944, Ozzie Nelson was prompted to create his own family situation comedy. The Adventures of Ozzie and Harriet launched on CBS on October 8, 1944, making a mid-season switch to NBC in 1949. The final years of the radio series were on ABC (the former NBC Blue Network) from October 14, 1949 to June 18, 1954. In total 402 radio episodes were produced. In an arrangement that amplified the growing pains of American broadcasting, as radio "grew up" into television, the Nelsons' deal with ABC gave the network the option to move their program to television. The struggling network needed proven talent that was not about to defect to the more established and wealthier networks like CBS or NBC.

The Nelsons' sons, David and Ricky, did not join the cast until the radio show's fifth year. The two boys were played by professional actors prior to their joining because both were too young to perform. The role of David was played by Joel Davis from 1944 until 1945. Tommy Bernard and Henry Blair appeared as Ricky. Other cast members included John Brown as Syd "Thorny" Thornberry, Lurene Tuttle as Harriet's mother, Bea Benaderet as Gloria, Janet Waldo as Emmy Lou, and Dick Trout as Roger. Vocalists included Harriet Nelson, The King Sisters, and Ozzie Nelson. The announcers were Jack Bailey and Verne Smith. The music was by Billy May and Ozzie Nelson. The producers were Dave Elton and Ozzie Nelson.