Drescher was born in Kew Gardens Hills, New York, the daughter of Sylvia, a bridal consultant, and Morty Drescher, a naval systems analyst. Her family is from Southeast and Central Europe. Her maternal great-grandmother Yetta was born in Focsani, Romania, and emigrated to the United States, while her father's family came from Poland. She has an older sister, Nadine.

In January 1985, two armed robbers broke into Drescher and Jacobson's Los Angeles apartment. While one ransacked their home, Drescher and a female friend were raped by the other at gunpoint. Jacobson was also physically attacked, tied up, and forced to witness the entire ordeal. It took Drescher many years to recover, and it took her even longer to tell her story to the press. She was paraphrased as saying in an interview with Larry King that although it was a traumatic experience, she found ways to turn it into something positive. In her book Cancer Schmancer, the actress writes: "My whole life has been about changing negatives into positives." Her rapist, who was on parole at the time of the crime, was returned to prison and given two life sentences.  After separating in 1996, Drescher and Jacobson divorced in 1999. They had no children. Drescher stated, "I would have been able to conceive but not hold on." Drescher has worked to support LGBT rights issues after her former husband came out. Drescher has stated that the primary reason for the divorce was her need to change directions in life. Drescher and Jacobson remain friends and business partners. She has stated that "we choose to be in each other's lives in any capacity. Our love is unique, rare, and unconditional; unless he's being annoying."  On September 7, 2014, Drescher and scientist and conservative politician Shiva Ayyadurai participated in a ceremony at Drescher's beach house. Both tweeted that they had married, and the event was widely reported as such. Ayyadurai later said it was not "a formal wedding or marriage", but a celebration of their "friendship in a spiritual ceremony with close friends and her family." The couple parted ways two years later.

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