(1984–1992), Jennifer Mancini in Melrose Place (1997–1998), Phoebe Halliwell in Charmed (1998–2006), Billie Cunningham in My Name Is Earl (2007–2008), Savannah "Savi" Davis in Mistresses (2013–2014), Renata Murphy in Wet Hot American Summer: Ten Years Later (2017), and Coralee Armstrong in Insatiable (2018–2019).

[5][6] Milano began her career at age seven, when her babysitter, without notifying her parents, took her to an audition for the national touring company of Annie.

After returning to New York, Milano appeared in television commercials,[7] and performed several roles in off-Broadway productions, including the first American musical adaptation of Jane Eyre.

[13] Subsequently, she starred in the children's film The Canterville Ghost, which did not achieve much praise or attention and Variety magazine noted in its review: "Milano as the catalyzing daughter Jennifer adapts to the ghostly Sir Simon without a qualm; that, of course, is the true charm of the story, but Milano doesn't exhibit enough presence to match the droll, charming Gielgud".

The film, which focuses on a group of young runaway and homeless teenagers,[21] was shot on and around Hollywood Boulevard[22] and was met with positive critical reception.

"[8] In the early 1990s, Milano auditioned for nearly every film role in her age bracket, including B movies,[8] and finally tried to shed her "nice girl" image by appearing nude in several erotic films targeted at adults, such as Embrace of the Vampire, Deadly Sins and Poison Ivy II: Lily.

In late 1996, Milano was offered a role of Jennifer Mancini on the drama Melrose Place by producer Aaron Spelling:[29] "We were looking for someone with sparkle.

[35] Milano was part of TBS's special coverage installment Hot Corner for the 2007 Major League Baseball playoffs.

[40] She has an interest in the Los Angeles Kings,[41] a National Hockey League team, and is involved with a related clothing line.

Milano has signed on to star in and produce My Girlfriend's Boyfriend, a romantic comedy in which she plays a woman with a relationship dilemma.

[46] Milano starred in the sitcom Romantically Challenged as Rebecca Thomas, a recently divorced single mother attorney in Pittsburgh who has not dated "since Bill Clinton was president".

[51] In 2013, Milano created the comic book series Hacktivist, which was written by Jackson Lanzing and Collin Kelly, drawn by Marcus To, and published by Archaia Entertainment.

The book, which explores the modern world of hacking and global activism, is described as "a fast-paced cyber-thriller about friendship and freedom in a time of war".

[53] In June 2013, she played Savannah Davis in ABC drama series Mistresses, which is about the scandalous lives of four girlfriends,[54] but she left the show after season two, due to conflict between filming location and family issues.

[58] In September 2015, Milano began to make appearances as a brand ambassador for the preschool television channel Sprout, being billed as the network's "mom-bassador".

[59] In 2017 and 2018, Milano joined the cast of two Netflix comedy series: Wet Hot American Summer: Ten Years Later[60] and Insatiable.

[70] She has appeared on the cover of numerous magazines, including Cosmopolitan, Stuff, Seventeen, Cleo, Woman's World, Veronica, Maxim and FHM.

[volume & issue needed] She has appeared in television commercials for Wen, Candies, Veet, Hi-C and Atkins diet.

[citation needed] In the late 1980s, Milano contacted Ryan White, a preteen boy ostracized for having AIDS, and a fan of hers.

[72] They appeared together on The Phil Donahue Show, where Milano kissed White on the cheek to emphasize that people do not catch the disease through casual contact.

[75] She raised approximately US$50,000 for South African women and children with AIDS by selling her own and schools' photo work.

Milano wrote on her blog that the latter trip was "the hardest experience I've had on a field visit", and described a waste dump close to the settlement where children spent time looking for metal to sell or scavenging for food.

[82] In September 2013, Milano released a parody of a celebrity sex tape on Funny or Die that drew attention to the Syrian civil war.

[91] In July 2018, and again in December 2020, Milano encouraged Twitter users to seek out VoteRiders to help eliminate confusion about voter ID laws.

[96] In May 2019, Milano advocated celibacy in the form of a sex strike in retaliation of a recently passed abortion law in the U.S. state of Georgia.

Publicly traded company's products being pushed in alignment with hate and white supremacy doesn't seem to be a winning business model."

[101] Following the Stoneman Douglas High School shooting, Milano co-founded #NoRA, a coalition of artists, activists, and survivors of gun violence in an effort to reduce the influence of the National Rifle Association of America in American government.

"[103] Milano helped raise money for Richard Dien Winfield,[104][105] a Democrat in Georgia's 2018 10th congressional district race.

"[120] In October 2023, Milano signed an open letter from several artists to Biden, calling for a ceasefire of the Israeli bombardment of Gaza.

[136][137] In 2015, Milano sold her condominium in West Hollywood and moved to Bell Canyon, California, where she owns land and her then nine horses, eight chickens, two rabbits, and five dogs.