Her father was a Pfizer executive and her mother Vijaya, the first wife of her father, was a nurse who specialized in suicide prevention. Her mother tongue is Tamil. She grew up shuttling between her grandparents in Chennai and her mother in New York. She is her parents' only child from this marriage. Her parents separated when she was age one. They divorced a year later. Both parents later remarried, and Lakshmi has a younger paternal half-brother and half-sister. The latter formerly worked as an actress and classical dancer but is now pursuing a career with children with special needs.
In 1984, when she was 14 years old, Padma was in a car accident in Malibu, California, causing an injury to her right arm that required surgery, which left a 7-inch scar between her elbow and shoulder.
On October 1, 2009, after years of struggling with endometriosis, a condition that causes pelvic pain and has been associated with infertility, Lakshmi confirmed that she was pregnant. Lakshmi also co-founded The Endometriosis Foundation of America, which is a nonprofit organization focused on increasing awareness, education, research, and legislative advocacy against the disease. On February 20, 2010, Lakshmi gave birth to a baby girl named Krishna Thea Lakshmi. Although the father's identity was not initially given, it was later revealed to be Adam Dell. In January 2011, Dell sued Lakshmi for sole custody of their daughter.