Since her mother's death from leiomyosarcoma cancer, Gilpin has led efforts for cancer research via the Sarcoma Foundation. Peri's sister, Patti Jo Wynne, and her step-siblings by her mother's second marriage, Marc and April Gilpin, also are actors.
Gilpin married the realist painter Christian Vincent on July 31, 1999. The couple have twins, Stella May and Ava, born via a surrogate mother on May 7, 2004. She is godmother to Frasier co-star Jane Leeves's daughter Isabella, and Jane is godmother to Peri's daughter Stella. Peri and Jane also live next door to each other in LA.