Harper married Thomas Edgar Rothman, a top executive at Sony Pictures (formerly of 20th Century Fox) on March 11, 1989 in an ecumenical ceremony. She has two daughters, Elizabeth and Nora, who are featured on her children’s albums and books. Harper resides in Los Angeles, California, and New York City.

She has written eleven books for children, and made seven albums of songs for children. She was named by Parenting magazine as “Parent of the Month” in 2004. In 2000, she sang background vocals on selected tracks on the Dan Hicks and his Hot Licks album Beatin’ the Heat.

Harper has appeared in more than twenty motion pictures, most notably in My Favorite Year, alongside Peter O’Toole and Mark Linn-Baker; and costarring with Steve Martin and Bernadette Peters in Pennies from Heaven. Woody Allen featured her in his films Stardust Memories and Love and Death. She appeared in the fourth season of It’s Garry Shandling’s Show and in the Steven Spielberg/Tom Cruise film Minority Report. She was seen in a 2005 episode (“Forget Me Not”) of the television series Crossing Jordan.

In December 2010, Harper released a cookbook titled The Crabby Cook Cookbook: Recipes and Rants. In a January 2011 interview Harper said, “I thought it was high time there was a book that acknowledged that not everybody experiences the joy of cooking, that sometimes cooking for a family on a daily basis can be really irritating! This book, with 135 easy recipes, is for those people, crabby cooks like me! It’s a collection of humor, survival tips and recipes, for the kitchen-challenged!” In March 2011, she was on tour promoting her book. Stops included Chicago, where she held a “Lunch and Learn with Jessica Harper”.

In a blog post on her official website in 2017, Harper revealed she had suffered from neovascular macular degeneration for the past 15 years, and that she receives injections in her eye every six weeks to treat the condition.