Rose first joined the Girlfriend model search in 2002, for which she came in second to Catherine McNeil. In 2010, she collaborated with the Australian fashion label Milk and Honey to design a capsule fashion line. The collection, named Milk and Honey Designed by Ruby Rose, includes washed jeans, leather jackets and T-shirts. The clothing line was available in selected retailers in Australia. Rose also released a collaboration collection with street footwear brand Gallaz.

In 2014, Rose began collaborating with Phoebe Dahl for their clothing range Faircloth Lane. She has featured predominantly within mainstream fashion titles, including Vogue Australia, InStyle Magazine, Marie Claire Magazine, Cleo, Cosmopolitan, Maxim, Nylon and New York's Inked Magazine. She's been the Australian ambassador for JVC, Australian clothes company JAG and luxury Danish label Georg Jensen. Rose is the face of Maybelline New York in Australia.

Since March 2016, Rose has been the face of Urban Decay Cosmetics.

In March 2017, Rose starred in Nike's latest campaign "Kiss My Airs" celebrating its Air Max Day. In May, Rose was the face of Swarovski 'Urban Fantasy' FW17 Collection launch.
In order to land her job as an MTV VJ in Australia, Rose competed against 2000 other hopefuls in a three-week national search, as former VJ Lyndsey Rodrigues moved to the United States to co-host TRL. As part of the competition, she downed 100 shots of beer in 100 minutes against Jackass's Bam Margera, and kissed strangers on a busy Sydney street. She stated, "Being a model there is always something they want to change. Whether they want someone a little bit skinnier, a little bit taller, a little bit prettier, but MTV wants you to be yourself ... not censoring anything and not conforming to anything."

In 2009, Rose won the ASTRA Award for Favourite Female Personality. She also travelled to Kenya to "highlight ... [the] amazing work" done by Global Vision International. She appeared in the episode "Media Virgins", of Australia's Next Top Model, acting as a guest judge, and also worked as a correspondent for the finale of Australia's Next Top Model.

In July 2009, Rose along with Dave Hughes, Charlie Pickering, Carrie Bickmore and James Mathison hosted The 7pm Project, an Australian television news talk show produced by Roving Enterprises which airs weeknights on Network Ten. She left the program to pursue her own hosting projects. In October 2009, it was announced that FOX8 had picked up the rights to UK format Ultimate School Musical, which features ordinary teenagers from a school attempting to put on a music product…

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Rose came out as a lesbian at age 12. She said that she was bullied, and that it included both verbal and physical abuse by her male peers, because of her sexuality and gender variance. She was also sexually abused as a child by a relative.

Rose experienced suicidal thoughts, and attempted suicide at age 12. She has struggled with mental health issues all of her life, having attempted suicide multiple times and has been diagnosed with complex post-traumatic stress disorder and clinical depression (which was initially misdiagnosed as bipolar disorder).

Rose said she was convinced she was a boy while growing up and that she was saving up money to physically transition from female to male. She said, "It was in my mind as something I wanted to do and then I just... didn't. I guess I grew out of it. I even used to sleep on my front because I didn't want to get boobs ever, which I think worked actually." Rose said she is glad she did not undergo gender-affirming surgery and that she desires to have children one day. She stated that modelling led her to discover androgyny, and allowed her to model with different gender expressions. She recalled, "I remember being at a yum cha restaurant with my dad and the owner coming up and saying, 'Excuse me, we're trying to work out if you're a handsome boy or a beautiful girl.' It was a compliment and I was shocked, and when I thought about it I actually wanted to be a handsome boy."

Rose is genderfluid, saying, "I am very gender fluid and feel more like I wake up every day sort of gender neutral." This announcement came approximately a week after she released Break Free, in which she visually transforms from a feminine presenting woman to a heavily tattooed masculine presenting person. Rose stated that she prefers to continue using feminine pronouns, but she also uses they/them pronouns. She said that if she had to choose a sex, she would choose to be male, but she does not feel like she should have been born with different body parts. Seeing the desire her transgender friends had for transitioning, she asked herself if her need to transition matched theirs, and concluded that she was satisfied being gender neutral. "I think at this stage I will stay a woman but ... who knows. I'm so comfortable right now I feel wonderful about it, but I also fluctuate a lot," she added.

In 2014, Rose was engaged to fashion designer Phoebe Dahl; in December 2015, they ended their romantic relationship. Rose was in a relationship with singer Jess Origliasso of The Veronicas from October 2016 to April 2018, having previously dated in 2008.

In 2019, Rose underwent emergency spinal surgery to treat two herniated discs caused by doing physical stunts on the set of Batwoman. She said if she had not had the surgery, she would have been at risk of being paralyzed.

Rose is a vegan.

Rose is a supporter of the Australian Football League team the Geelong Cats.

Various media outlets have commented on public fascination with Rose's gender identity, gender expression, and physical appearance, including her tattoos and visual or behavioral similarities to Angelina Jolie, Justin Bieber, and a younger Leonardo DiCaprio. In 2008 and 2009, she was chosen as one of the "25 Most Influential Gay and Lesbian Australians" by SameSame, an Australian online gay and lesbian community. The public and media attention increased following Rose's debut on Orange Is the New Black, significantly with regard to heterosexual women commenting on her physical appearance. During 2015, she was the fifth-most-searched person on Google. PETA named her one of three "Sexiest Vegans" of 2017.

Emma Teitel of Maclean's stated, "Rose ... resembles an androgynous Angelina Jolie; she is a rare combination of angular and soft. She is a badass with a permanently arched brow and a Justin Bieber haircut. In other words, she is the lesbian James Dean. And straight women are falling madly in love with her." Alex Rees of Cosmopolitan said that everyone was enamored of Rose at the time of her season three appearance on Orange Is the New Black.

Rose acknowledged the public discourse concerning her physical appearance and subsequent debate on sexual fluidity after heterosexual women said they would "go gay" for her, commenting that while she thought it was brilliant and was neutral on the matter, some found the public affection toward her inappropriate because they believe it implied people can choose to be gay. Rose said she believes people are being complimentary when making such comments rather than trying to be derogatory or diminish the coming out process. She said today's society is more open about sexuality than in the past and that people should not nitpick who can or cannot identify as genderqueer, gender-neutral, bisexual or trans, or tell them how to live their lives, and that this is a message the LGBT community should be supporting.