In 1997, she was cast as Meadow Soprano, daughter of New Jersey mob boss Tony Soprano. The show premiered in 1999 and became a huge success, catapulting Sigler to fame as a TV Actress. She continued to play the role through the series finale in 2007.

In 2000, while filming Campfire Stories in Hamburg, New Jersey, Sigler was paralyzed from the waist down for several days by Lyme disease. Sigler played the title role in Cinderella on tour and at The Theatre at Madison Square Garden in 2001. She then spent five months on Broadway from October 2002 through February 2003 playing Belle in Beauty and the Beast. She has continued to appear in theatrical roles.

In 2001, she released a pop album called Here to Heaven, which featured the single "Cry Baby". The album was a commercial failure. In 2007, Sigler said she was "embarrassed" by the album and regretted releasing it. In 2012, she collaborated with Romeo Santos on the single "You" and appeared in its music video.

In 2002, she co-authored an autobiography, Wise Girl: What I've Learned About Life, Love, and Loss.

Sigler met Abraxas "A. J." DiScala when she was 19, and he became her manager. They began dating shortly before she turned 21, and married on July 11, 2003. She subsequently changed her name to Jamie-Lynn DiScala. In September 2005, Sigler and DiScala separated, and she resumed using her maiden name.

She appeared in FHM and was featured in The Girls of FHM 2004.

In 2008, Sigler visited Israel through the Birthright Israel program and was moved by the trip, calling Israel "one of the most beautiful, inspiring places I've ever been to". She said that the trip gave her a greater understanding to preserve her Jewish identity. Also in 2008, Sigler began a relationship with actor Jerry Ferrara, whom she met while guest-starring on Entourage as a love interest of Ferrara's character, Turtle. They split up in 2009. She then dated football player Mark Sanchez.

In 2009, she starred in the psychological thriller film Beneath the Dark, which originally had a working title of Wake. The same year, she appeared on ABC's Ugly Betty in a five-episode arc. Beginning in 2012, she appeared as a main character in the short-lived series, Guys with Kids.

In 2012, Sigler began dating baseball player Cutter Dykstra, the son of former Major League Baseball player Lenny Dykstra. The two became engaged on January 28, 2013, and announced in February 2013 that they were expecting a baby. Sigler gave birth to their son, Beau Kyle Dykstra, on August 28, 2013. They were married in Palm Springs, California on January 16, 2016. The couple welcomed their second son in January 2018.

Sigler was born in Jericho, New York, the daughter of Steve and Connie Sigler. She has a brother, Brian, and Adam, who died in November 2014. Her father was the founder of the Men's Senior Baseball League and is of Sephardic Jewish (via Greece) and Romanian Jewish descent. Her Cuban mother was raised Catholic and converted to Judaism upon marrying Sigler's father. Sigler began acting and singing at the age of seven. She went to Hebrew school and had a bat mitzvah. She attended Jericho High School. She also studied at the Cultural Arts Playhouse in Old Bethpage.

In January 2016, Sigler revealed that she was diagnosed with multiple sclerosis when she was 20 years old.