Rebel Melanie Elizabeth Wilson was born on 2 March 1980 in Sydney, New South Wales, Australia. Her parents are professional dog handlers, dog show judges and breeders. Wilson grew up in the suburbs of Kenthurst, Parramatta and Castle Hill. She attended the independent Tara Anglican School for Girls as a boarder. She completed her Higher School Certificate in 1997, achieving a ranking of 99.3, including second place in the state in Food Technology. Wilson joined the debating team and a teacher encouraged her to enter Tournament of Minds which she credits for helping her come out of her shell. Wilson worked at a cinema in Castle Hill in her younger years, but quit after patrons recognised her after the showing of her first movie, Fat Pizza.

Wilson has three siblings: sisters Liberty and Annaleise (who uses the name "Annarchi") and a brother, who uses the name "Ryot". Liberty and Ryot appeared on the first season of The Amazing Race Australia in 2011, where they were the first team eliminated. Wilson has stated that, according to her grandmother, her great-aunt was Lillian Disney, who was married to Walt Disney until his death in 1966. Wilson stood by this belief in court, despite there being no evidence to support the claim; it continues to be disputed by genealogist Dale Sheridan.

Wilson studied at the Australian Theatre for Young People (ATYP). In 2003, she moved to New York after winning the ATYP International scholarship, which was funded by Nicole Kidman. While in New York, Wilson trained with The Second City. She appeared with the Sydney Theatre Company and performed at the Melbourne International Comedy Festival. She first came to the public's attention in 2002 with her stage musical The Westie Monologues, which she wrote, starred in and produced in Sydney. Her follow-up stage productions, which she wrote, produced and starred in include Spunks and Confessions of an Exchange Student.

In Australia, Wilson is most known for her roles as Toula on the SBS comedy series Pizza and as various characters including Lucy, Fat Mandi and Karla Bangs on the sketch comedy series The Wedge. She played an Australian Idol mad schoolgirl in a series of Telstra advertisements shown during Australian Idol from 2004 to 2005. She also had roles in the feature films Fat Pizza (2003) and Ghost Rider (2007).

In 2008, Wilson created, wrote, produced and starred in the musical comedy series Bogan Pride on SBS One and also starred in the improvisational Nine Network series Monster House. In 2009 Wilson won the Tropfest Best Actress award for her role in the film Bargain. She has made appearances on the improvisational comedy show Thank God You're Here and the comedy game show Talkin' 'Bout Your Generation. She performed stand-up on the television special The Breast Darn Show In Town and guest starred in the Seven Network drama City Homicide and performed improv at the Upright Citizens Brigade in Los Angeles.

Not content with her small role in Ghost Rider, Wilson moved to the United States in January 2010 and signed to talent and literary agents William Morris Endeavor. Wilson's next film role came in the Judd Apatow film, Bridesmaids, in which she played Brynn, the sister of Matt Lucas' character. The role was written especially for her. Wilson then appeared in the CBS sitcom Rules of Engagement and on the Comedy Central series, Workaholics. She co-hosted the 2010 ARIA Music Awards and performed at the inaugural Variety's Power of Comedy event in Los Angeles with Lucas and Russell Brand. In early 2011, Wilson filmed A Few Best Men at Fox Studios Australia. She also filmed a role in Small Apartments. Wilson was named one of Variety magazine's "Top Ten Comics to Watch for 2011". In 2012, Wilson had a role in the ensemble comedy What to Expect When You're Expecting, as Janice and co-starred in the indie film Struck By Lightning.