In the mid-1960s, she appeared on the Australian music show Bandstand. In one appearance, she sang a 1920s-style pastiche, the novelty song "I Love Onions."

In 1963, at the age of 16, Jacki mimed the role of Gretel to the great Soprano, Marilyn Richardson, in an ABC production of Weber's Hansel and Gretel, conducted by Sir Charles Mackerras. In 1964 at the Palace Theatre in Sydney, Weaver and a number of other Australian Singers such as The Delltones and her then-boyfriend Bryan Davies performed a satire on the Gidget movies, in which Weaver performed as "Gadget."

Weaver had a relationship of many years with Richard Wherrett, Director of the Sydney Theatre Company. She was married to David Price from 1966 to 1970 before marrying Max Hensser in 1975. She lived with Phil Davis, former Sydney crime reporter, Canberra Press Secretary and Executive Producer for Mike Willesee, for five years in "the most stable relationship of her life" until 1981 before she married radio and television presenter Derryn Hinch in 1983. She and Hinch divorced in 1996, remarried in 1997, and divorced again in 1998. She had a son, Dylan (b. 1969) with partner at the time John Walters. She is currently married to actor Sean Taylor.

Weaver emerged in the 1970s as a symbol of the Australian New Wave through her work in Ozploitation films such as Stork (1971), Alvin Purple (1973) and Petersen (1974). In 2005, she released her autobiography titled Much Love, Jac.

Weaver's film debut came with 1971's Stork for which she won her first Australian Film Institute Award. In the 1970s, Weaver gained a sex-symbol reputation thanks to her performances in the likes of Alvin Purple (1973), a stereotyping she claimed she hated, but complied with as a means to work. Other notable films during this time include a small role in Peter Weir's critically acclaimed film version of Picnic at Hanging Rock (1975), and a more substantial appearance in Caddie (1976) for which she won her second Australian Film Institute Award.

Jacki's racy appearances in television shows such as No. 96 and The Box, threatened to seal her as a sex symbol, but this was challenged by her stage work in Chekov's The Cherry Orchard and Tennessee Williams' A Streetcar Named Desire, in which she played Stella. Her stage abilities were recognised with a "Mo" award. In 1980 she appeared in a television production of Summer Locke Elliot's Water Under the Bridge.

In the 1990s and early 2000s, Weaver found it increasingly difficult to gain roles on screen or television and she devoted much of her Energy to the Australian stage, starring in plays including A Streetcar Named Desire, Last of the Red Hot Lovers, Death of a Salesman, Reg Cribb's Last Cab to Darwin, and Chekhov's Uncle Vanya alongside Cate Blanchett and Richard Roxburgh in 2010-11.

Weaver is a supporter of the Australian Labor Party, and recorded a radio advertisement in support of them for the 1996 federal election.

In 2010, Weaver starred in the Melbourne-set crime thriller Animal Kingdom playing a gang family matriarch. Her dead-pan performance earned her an Academy Award nomination as well as winning the Australian Film Institute Award, the National Board of Review, Los Angeles Film Critics Association Award and a Satellite Award.

In August 2013, Australians in Film announced that Weaver would be honoured with the organisation's Breakthrough Award at an exclusive Benefit Dinner held 24 October 2013 in Los Angeles. She also portrayed Dr. Warren in the 2014 comedy crime horror film The Voices.