At 15, while attending Geelong Grammar’s Timbertop, she wrote “All for Believing” for a school music assignment, completing it just hours before the deadline. The assignment earned an A and she performed her song in front of classmates. She approached a Melbourne record company and was told that they wanted more than one song. She wrote more songs and worked with the Kool Skools project, which enables students to record music. In 2001, Missy’s sister Nicola entered “All for Believing” on her behalf in Unearthed, radio station Triple J’s competition for unsigned artists. The song won the competition and was added to the station’s play list.

Higgins was the support act on a 2003 Australian tour by folk rock band The Waifs and rock band george. She travelled to the US to work with John Porter, who produced her first EP, The Missy Higgins EP, which was released in November and entered the Australian Recording Industry Association (ARIA) Singles Chart Top 50 in August 2004.

She toured Australia, supporting Pete Murray and John Butler Trio. Her four-track single “Scar'” was released in July 2004 and debuted at No. 1 on the ARIA Charts. Her first album, The Sound of White, was released in September, and debuted at No. 1 on the ARIA Albums Chart. Also produced by Porter, it sold over 500,000 copies. She was nominated in five categories at the ARIA Music Awards of 2004 for “Scar”: Best Female Artist’, ‘Single of the Year’, ‘Best Pop Release’, ‘Breakthrough Artist – Single’ and ‘Best Video’ (directed by Squareyed Films). At the awards ceremony on 17 October she received the award for Best Pop Release, beating Delta Goodrem, The Dissociatives, Kylie Minogue and Pete Murray. This was followed by her first national headline tour. Her second single “Ten Days” was co-written with Jay Clifford (guitarist in US band Jump, Little Children) and was inspired by Higgins’ 2002 break-up with her boyfriend before she travelled to Europe. Released in November, it peaked at No. 12.

From 2004 to 2007, Higgins’ sexual orientation was the subject of media speculation based partly on interpretations of her lyrics and her interviews. In an October 2007 interview with Australian lesbian magazine Cherrie, she was asked if she fell under the moniker of “not-so-straight” girls. She replied “Um, yeah, definitely. … I think sexuality is a fluid thing and it’s becoming increasingly more acceptable to admit that you’re that way.” In November her Myspace page reported, “I’ve been in relationships with both men and women so I guess I fall most easily under the category ‘Bisexual'”.

On 29 January 2005 Higgins performed with other local musicians including Nick Cave and Powderfinger at the WaveAid fundraising concert in the Sydney Cricket Ground. The concert raised A$2.3 million for four charities supporting the victims of the 2004 Indian Ocean earthquake. In March Higgins performed at the MTV Australia Awards and won the prize for ‘Breakthrough Artist of the Year’. The following month she released her third single, “The Special Two”, which was a radio hit and reached No. 2. “The Special Two” was released on an EP which included her cover of the Skyhooks song, “You Just Like Me Cos I’m Good in Bed”, recorded for Triple J’s 30th anniversary. The song had been the first track played on Triple J when it launched (as Double J) in 1975. In May, Higgins won the ‘Song of the Year’ and ‘Breakthrough’ awards for “Scar” from the Australasian Performing Right Association (APRA). She continued touring in mid-2005 and released her fourth single, “The Sound of White”, in August. In September she played a sold-out performance at the Vanguard in Sydney with the proceeds going to charity. She was nominated for seven more ARIAs and in October won ‘Album of the Year’, ‘Best Pop Release’, ‘Breakthrough Artist – Album’ and ‘Highest Selling Album’ (all for The Sound of White) and ‘Best Female Artist’ (for “Scar”). She teamed up with fellow ARIA award-winning singer Ben Lee in late 2005 for a national tour.

As a vegetarian, Higgins promoted the health benefits of not eating meat in a 2005 advertising campaign by People for the Ethical Treatment of Animals (PETA); and has supported their anti-fur stance. She is interested in environmental issues and is involved with the Sierra Club, a grassroots organisation based in California. She has protested against the proposed industrialisation of the Kimberley region of Western Australia and donated the royalties from her 2009 EP More Than This. Since early 2007, Higgins has tried to make her tours carbon neutral, she purchases green energy to power venues, uses hybrid cars where possible and purchases carbon offsets.

During 2006, Higgins lived in Broome, Western Australia for six months, away from the entertainment industry. The relaxed lifestyle helped her focus on writing new material. The landscape made a big impression, “It was the first place I’d ever felt honestly connected with my country, with the physical land of my country” and inspired her to write “Going North”. She then toured the United States and South Africa, writing more material on the road. In September she based herself in Los Angeles to record her second album, On a Clear Night, with producer Mitchell Froom. “Steer” was released as an EP, followed a fortnight later by its album on 28 April 2007, both debuted at No. 1 on their respective charts.

Higgins has been a patron of multiple mental health charities since 2003. She described her younger self as “a bit of a depressed child” and “introverted”, and that she had “experienced various degrees of depression”. Prescribed antidepressant medication while in high school, she learned to channel low moods into songwriting, calling music her “emotional outlet”. In a 2006 interview she said that her songs were “coming from more of a happier place”. While recording her second album she discovered a passion for rock climbing, as a “meditative pursuit” and that, “It’s the first and last thing I’ve had – other than music – that I’m passionate about.”

On a Clear Night, was released in the US on 26 February 2008, supported by a tour in March. Her ten-month stay in Los Angeles during 2008 promoted her songs for films and television shows. Her first US single “Where I Stood” was featured in US series including Grey’s Anatomy, One Tree Hill and So You Think You Can Dance. During 2008, Higgins supported the Indigo Girls and then Ben Folds on their respective US tours. February and March 2009 saw her co-headlining a US tour with Canadian Justin Nozuka. On 31 March she released an EP, More Than This in Australia that features cover versions of “More Than This” by Roxy Music, “(I’m) In Love Again” by Peggy Lee, “Breakdown” by Tom Petty and “Moses” by Patty Griffin. “Moses” had been included on Triple J’s 2005 compilation album Like a Version: Volume One and “More Than This” was recorded as part of Covered, A Revolution in Sound, a Warner Bros. tribute album also released in March 2009.

Higgins started writing music for her third album in 2009. After about seven years of touring and recording she took a break from the music industry to pursue other interests. In 2010 she enrolled in a course in indigenous studies at the University of Melbourne. Her acting debut was as Annie in 2010 film Bran Nue Dae directed by Rachel Perkins. The film is an adaptation of the 1990 musical, Bran Nue Dae, “Australia’s first Aboriginal musical”. Although Higgins would consider future acting projects she has no plans to actively pursue it as a career.

In July and August 2010, Higgins played several dates of Sarah McLachlan’s Lilith Fair tour in the US. At Lilith Fair, she met Australian musician Butterfly Boucher and they decided to work together. In 2011, Higgins travelled to where Boucher was living in Nashville to record her third album, which is co-produced by Boucher and Brad Jones. Titled The Ol’ Razzle Dazzle, the album was released on 1 June 2012. Its first single, “Unashamed Desire”, co-written with Boucher, was released on 23 April. In November 2011, at the ARIA Music Awards, Higgins performed a duet of “Warwu”with Geoffrey Gurrumul Yunupingu, from his Rrakala album.

On 7 September 2012, Higgins recorded a cover version of Gotye’s “Heart’s A Mess” for the “Like a Version” segment on Australian radio station Triple J, explaining on-air that the song is her favourite Gotye composition. Higgins had travelled with Gotye previously and referred to him as “an incredible singer” in the interview prior to the rendition.

On 5 October 2012, Higgins performed at two “Save the Kimberley” events held at Federation Square in Melbourne and The Esplanade in Fremantle, Western Australia. A march to protest against the proposed gas refinery construction at James Price Point accompanied the free concert and campaign supporters were photographed with banners and placards.

As of 2012, Higgins is one of numerous publicly known advocates for the ‘Oscar’s Law’ campaign. The campaign, launched in 2010, protests against the existence of “puppy factories” in Australia, whereby animals are factory farmed. One of the campaign’s slogans is “Break the Puppy Trade—Don’t buy puppies from pet shops” and the list of notable advocates includes Paul Dempsey (musician), Kate Ceberano (singer) and Mick Molloy (comedian).

In 2013, Higgins began a relationship with Broome playwright and comedian Dan Lee. Higgins gave birth to a son in 2015. Higgins and Lee were married in March 2016, and she gave birth to a daughter in 2018.

In September 2014, Higgins released her fourth studio album, Oz, which features cover versions of Australian composers, including The Angels, Slim Dusty, Something For Kate, Warumpi Band, Paul Kelly and The Drones. The album is also accompanied by a book of related essays, in which Higgins uses each of the recordings to reflect upon subjects such as music and love. Higgins collaborated with Dan Sultan for the recording of the Slim Dusty song “The Biggest Disappointment”.

The national Australian tour in support of Oz commenced on 20 September 2014 in Cairns, Queensland, and ended in Melbourne in October 2014. Higgins was accompanied by Bischoff, and Australian artist Dustin Tebbutt appeared as a special guest.

In response to the proposed dumping of around 3 million cubic metres (110 million cubic feet) of dredged seabed onto the Great Barrier Reef, a legal fighting team was formed by World Wide Fund for Nature (WWF)-Australia and the Australian Marine Conservation Society (AMCS) in late 2013/early 2014. The legal team received further support in April 2014, following the release of the “Sounds for the Reef” musical fundraising project. Produced by Straightup, the digital album features Higgins, in addition to artists such as The Herd, Sietta, John Butler, The Cat Empire, Fat Freddys Drop, The Bamboos (featuring Kylie Auldist) and Resin Dogs. Released on 7 April, the album’s 21 songs were sold on the Bandcamp website.

On 19 February 2016, Higgins released a new single titled, “Oh Canada”, in her response to the death of Alan Kurdi.

In May 2017, Higgins released “Torchlight”, for the Australian drama film, Don’t Tell.

In October 2017, Higgins appeared in a revival of the 1996 musical Miracle City by Nick Enright and Max Lambert at the Sydney Opera House, playing the role of Bonnie Mae.

In February 2018, Higgins released the single “Futon Couch”, the first single from her fifth studio album, called Solastalgia, released in May 2018.

In February 2018, it was announced that Missy Higgins would support Ed Sheeran’s tour around Australia.

In November 2018, Higgins released her first greatest hits album titled The Special Ones.

In October 2019, new music by Higgins featured in the Australian television series Total Control.

In the 2020 Australian documentary film Slim and I, directed by Kriv Stenders, Higgins paid tribute to the influence on her life and career of acclaimed Australian country music singer-songwriting couple Slim Dusty and Joy McKean. The film features interviews and covers of McKean songs by acclaimed contemporary artists including Higgins (The Biggest Disappointment), Keith Urban, Paul Kelly, and Troy Cassar-Daley.