Irene Ryan began her career at the age of 11, after winning $3 for singing “Pretty Baby” in an amateur contest at the Valencia Theater in San Francisco. At 20, she married writer-comedian Tim Ryan. They performed in vaudeville as a double act, known in show business as a “Dumb Dora” routine and epitomized by George Burns and Gracie Allen. (According to Jim Jordan Jr., while playing the same circuit as Marian and Jim Jordan, Ryan suggested they include more comedy and patter in their show, which led to the creation of Fibber McGee and Molly.) Billed as “Tim and Irene”, they had their own series of short subjects in the 1930s for Educational Pictures, and later worked in feature films for Monogram Pictures. Substituting for Jack Benny in 1936, they starred in The Jello Summer Show on NBC’s “Red” Network. Recordings (made on 78 rpm 12″ lacquer disks) of the shows of September 20 and September 27 (the latter the last of the series) exist. Don Wilson, Benny’s announcer, was on those two shows. Tim and Irene Ryan had no children and divorced in 1942, although she kept his surname. She toured with Bob Hope and was on his radio program for two years. She played Edgar Kennedy’s wife in two of his series of short films in 1943. That same year, she appeared in the country music film O, My Darling Clementine.

In 1944, Irene Ryan played a ditzy secretary named Polly in a B-Movie titled Hot Rhythm with Dona Drake. In 1946, she married Harold E. Knox, who worked in film production. (She and Knox divorced in 1961; the couple had no children.) She continued to work in motion pictures of the late 1940s and early 1950s, generally playing fussy or nervous women. In January 1955, Ryan made her first television sitcom appearance on an episode of CBS’ The Danny Thomas Show. She appeared with Walter Brennan in an episode of his ABC sitcom, The Real McCoys. In the 1960–61 CBS sitcom, Bringing Up Buddy, starring Frank Aletter, she was cast in three episodes as “Cynthia Boyle”. In 1946, she joined the cast of The Jack Carson Show on CBS radio. She played “a neighborhood storekeeper who operates a combination candy shop and lending library.” After her divorce from Knox the prior year, Irene Ryan was cast in 1962 as Daisy “Granny” Moses, the mother-in-law of patriarch J.D. “Jed” Clampett in The Beverly Hillbillies. According to Filmways publicist Ted Switzer, series creator and producer Paul Henning had decided to cast Bea Benaderet as Granny. However, when Ryan read for the role, “with her hair tied back in a bun and feisty as all get-out”, she just blew everyone away. Executive producer Al Simon and Henning immediately said: “That’s Granny”. Later, when Benaderet saw Ryan’s tryout, she agreed. Benaderet was cast as Jed Clampett’s cousin, Pearl Bodine. On March 10, 1973, Irene Ryan suffered an apparent stroke during a performance of Pippin. She flew home to California on her doctor’s orders and was hospitalized. She was diagnosed with a glioblastoma (malignant brain tumor), although was reportedly not informed of the fact. She died at St. John’s Hospital, Santa Monica, California on April 26, 1973, aged 70. Her body was interred in a mausoleum crypt at the Woodlawn Memorial Cemetery in Santa Monica beside her sister, Mrs. Anna Thompson.