Alongside her music career, Higgins pursues interests in animal rights and the environment, endeavouring to make her tours carbon neutral.

[2] Higgins learned to play classical piano from age six, following in the footsteps of Christopher and David, but realised she wanted to be a singer at about 12, when she appeared in an Armadale Primary School production of Andrew Lloyd Webber's musical Joseph and the Amazing Technicolor Dreamcoat.

[7] In 2001, Missy's sister Nicola entered "All for Believing" on her behalf in Unearthed, radio station Triple J's competition for unsigned artists.

"[10] The backpacking trip had been planned with a friend for years and the pair spent most of 2002 in Europe; while Higgins was travelling, "All for Believing" started to receive airplay on Los Angeles radio station KCRW.

[19] Her second single "Ten Days" was co-written with Jay Clifford (guitarist in US band Jump, Little Children) and was inspired by Higgins's 2002 break-up with her boyfriend before she travelled to Europe.

[14] 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.

[14] "The Special Two" was released and included her cover of the Skyhooks song, "You Just Like Me Cos I'm Good in Bed", recorded for Triple J's 30th anniversary.

[14] In February, Higgins had contributed a tribute song to the album, Cannot Buy My Soul, for noted indigenous singer, Kev Carmody, singing "Droving Woman" with musician Paul Kelly and group Augie March.

She sang headline act Powderfinger's "Sunsets" with front man Bernard Fanning and joined in with the encore of "These Days".

[32][44] Her first US single "Where I Stood" was featured in US series including Smallville, Grey's Anatomy, Ghost Whisperer, One Tree Hill and So You Think You Can Dance.

[58] In November 2011, at the ARIA Music Awards, Higgins performed a duet of "Warwu" with Geoffrey Gurrumul Yunupingu, from his Rrakala album.

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.

[64] The national Australian tour in support of Oz commenced on 20 September 2014 in Cairns, Queensland, and ended in Melbourne in October 2014.

[66] 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.

[78] Higgins grew up in the 1980s and 1990s listening to artists that her older siblings liked—Nicola played Mariah Carey and Whitney Houston, while David favoured Queen and Kiss.

[79][80] Departing for boarding school at age 13, she was exposed to alternative artists like Nirvana and Hole and started teaching herself guitar and writing her own music.

[4][49][81] Material from her third album is influenced by ambient music from Low, Jon Hopkins, Icelandic band Sigur Rós and Estonian classical composer Arvo Pärt.

[49] Higgins's songwriting grew out of a desire to express her emotions when she was at school, and her lyrics describe her feelings about her own life and relationships.

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.

[103] In October 2012, Higgins also performed at two "Save the Kimberley" events held at Federation Square in Melbourne and The Esplanade in Fremantle, Western Australia;[104][105] 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.

In 2016, Missy Higgins released "Oh Canada", which was written from the perspective of the refugee father of Alan Kurdi,[127][128] a two-year-old Syrian boy who drowned while fleeing to Europe.

[129] In 2017 Higgins was announced as a new ASRC Ambassador[129] and in 2018 appeared on ABC's Q&A program and expressed her views on the Australian Government's treatment of asylum seekers.

[130] Higgins also featured in the 2022 documentary 'Scattered People: A Song Can Take You Home'[131][132] presented by the ASRC and Being Reel Films, along with other Australian Musicians.

[131] Rolling Stone Australia called Higgins's soundtrack for the second season of the ABC drama Total Control an "outspoken fight for equality",[133] and the work was inspired by Grace Tame and Brittany Higgins and the 2021 Australian Parliament House sexual misconduct allegations,[134] with themes of exploitation and female empowerment.

[137] Higgins also headlined the all-female festival tour Wildflower[138][139] in 2022 alongside Kate Miller-Heidke, Kasey Chambers, Sarah Blasko, Deborah Conway, Thornbird and Alice Skye in order to celebrate women and the return of the live scene.

In 2007 she joined the Oxfam Australia 'Close the Gap' campaign[144] and recorded a cover of 'Droving Woman' with Augie March on the tribute album to Kev Carmody, an Aboriginal Australian singer-songwriter and musician.

[145] The song begins with a sample from the 2008 Formal Apology to the Stolen Generations made by former Australia Prime Minister Kevin Rudd.

[148][149] She also performed the song with Minchin at the streamed charity concert Music from the Home Front which paid tribute to the Australian and New Zealand Army Corps and workers on the frontline of COVID-19 pandemic responses.

[13][158] Prescribed antidepressant medication while in high school, she learned to channel low moods into songwriting, calling music her "emotional outlet".

[159] While recording her second album, she discovered a passion for rock climbing, as a "meditative pursuit"[160][79] From 2004 to 2007, Higgins's sexual orientation was the subject of media speculation based partly on interpretations of her lyrics and her interviews.