Alyssa's mother was Lin, a fashion designer and talent manager and her father was Thomas M. Milano, a film music editor and boating enthusiast. Both of her parents were of Italian-American backround. Alyssa was born in Brooklyn and grew up in Staten Island, and was raised Roman Catholic. She has a younger brother, Cory who was born in 1982. He is also an actor. In a 2003 interview, Alyssa Milano recalled having had a good childhood, having grown up in a "loving, true family."
Milano has dyslexia. In an interview in 2004, Milano explained how she deals with the disorder: "I've stumbled over words while reading from teleprompters. Sir John Gielgud, whom I worked with on The Canterville Ghost years ago, gave me great advice. When I asked how he memorized his monologues, he said, 'I write them down.' I use that method to this day. It not only familiarizes me with the words, it makes them my own."
Milano is a fan of the Los Angeles Dodgers and writes a regular baseball blog on the Major League Baseball's website. In 2007, Milano launched her signature "Touch" line of team apparel for female baseball fans, selling it through her blog and Major League Baseball's website. It also became available in 2009 through a boutique store located in Citi Field, the home of the New York Mets.
She has an interest in the Los Angeles Kings, a National Hockey League team and is involved with a related clothing line. In 2008, she expanded that to NFL football, as a New York Giants fan. Since Milano is in the same hometown as NFL Network's Rich Eisen (Staten Island), she revealed some of her family's connections with the New York Giants.
Alyssa has eight tattoos on her body: one on each wrist and ankle, shoulder, neck, hip, and lower back. She is a Vegetarian and appears in numerous PETA advertising campaigns for vegetarianism. Outside of acting, her hobbies include photography, humanitarian work, and spending time with her three dogs and eight horses. Alyssa has commented on her love for animals, and in a 2009 interview discussed one of her dogs, a German Shepherd called Pinto, who had died at the age of 14; he had worked with the LAPD dogs and Alyssa had owned him for 10 years.
Milano dated actor Corey Haim from 1987 to 1990. She was engaged to Scott Wolf in 1993. She was married to singer–songwriter Cinjun Tate of Remy Zero in 1999; they were divorced later that year. She dated Charmed co-star Brian Krause for a while during the third and fourth season of the show. She briefly dated Justin Timberlake in 2002. After one year of dating, she and CAA agent David Bugliari were engaged December 18, 2008. Milano and Bugliari married on August 15, 2009 in New Jersey, at the home of Bugliari's family.