After The Ann Sothern Show ended, she returned to films in 1964's The Best Man, opposite Henry Fonda. She was nominated for a Best Supporting Actress Golden Globe for her work in the film. That same year, she portrayed a prostitute in the psychological thriller Lady in a Cage (1965), starring Olivia de Havilland. In 1965, she had a recurring role on her friend Lucille Ball's The Lucy Show as the "Countess Framboise" (née Rosie Harrigan). After Ball's long-time co-star Vivian Vance announced plans to leave the show, the press speculated that Sothern would be Vance's replacement. Sothern denied the rumors and, ultimately, the series continued without Vance or Sothern.
In 1965, Sothern co-starred in the TV comedy series My Mother the Car, opposite Jerry Van Dyke. The show was typical of then-popular situation comedies featuring a flying nun (The Flying Nun), a talking horse (Mister Ed), a domestic witch (Bewitched), or other surreal premises. Van Dyke played a struggling lawyer and family man who discovers a dilapidated, vintage 1928 automobile in a used-car lot. The antique auto speaks to him — in Ann Sothern's voice. It seems the car is the reincarnation of Van Dyke's mother. Van Dyke restores the car to its original condition and takes it home, where it bemuses his family and becomes the envy of a zealous collector. Sothern was never seen in the series; only her voice was heard, reacting tartly to zany happenings around her.