The 39-year-old actress and her 36-year-old husband, Will Kopelman, are welcoming their second daughter.
Barrymore's rep, Chris Miller, confirms Frankie Barrymore Kopelman was born Tuesday.
Barrymore and Kopelman's first child, daughter Olive, is 19 months old.
The couple say in a statement that "Olive has a new little sister, and everyone is healthy and happy!"
Barrymore told The Associated Press earlier this month that becoming a parent is the greatest thing she's ever done in my life.
Barrymore's latest film, out May 23, is the family-friendly comedy "Blended," which co-stars Adam Sandler. Her recent photo book, "Find It in Everything," was dedicated to daughter Olive.