Her modeling career began at the age of 17, after getting signed to Vivien's Management in Sydney. Soon after she moved to Paris and started working as a runway model for Karl Lagerfeld, Issey Miyake, Chanel, Emanuel Ungaro, Gianfranco Ferré, Givenchy, Alberta Ferretti, Kenzo, Valentino and Oscar de la Renta. She appeared in campaigns for Bonds, L'Oréal, Revlon, Ralph Lauren, Yves Saint Laurent, and Estée Lauder, as well as the 1999 and 2003 Sports Illustrated Swimsuit issues. Her magazine covers include Vogue, Elle, Marie Claire, Glamour, GQ and Harper's Bazaar. She has appeared on magazine issue covers in Australia, Spain, the United Kingdom, and the United States.

In 1999, the then-Sarah O'Hare married Lachlan Murdoch, the eldest son of Australian-born American media mogul Rupert Murdoch. The couple resides in Brentwood, Los Angeles, California with their two sons, Kalan Alexander, (born 9 November 2004), Aidan Patrick, (born 6 May 2006) and their daughter, Aerin Elisabeth Murdoch (born 12 April 2010).

Murdoch is engaged in assisting not-for-profit arts and charitable bodies. She was appointed International Ambassador of the Australian Ballet Company in 2004 and joined The Australian Ballet Board of Directors in 2006. She is also ambassador of the Murdoch Children's Research Institute and a member of its development board. The Institute was established in 1986 by her husband Lachlan's grandmother, Dame Elisabeth Murdoch and is the largest child health research institute in Australia. Murdoch is patron of Australia's National Breast Cancer Foundation, and addressed the National Press Club of Australia about the activities of the foundation on 4 October 2006 and again on 24 December 2008. The addresses were televised Australia-wide by the Australian Broadcasting Corporation. Murdoch is a keen rugby league fan and supports the Manly Sea Eagles.

Murdoch filled in for Jessica Rowe on the popular morning news and interview show, Today while Rowe was taking four months maternity leave. On 26 March 2007, it was reported in the Sydney Morning Herald that Murdoch would finish up her hosting duties on Today as of 30 March 2007. Nine News presenter Kellie Sloane replaced Murdoch until May 2007, when Lisa Wilkinson took over as the new co-host on Today. Murdoch returned as a guest host on the 4 October 2007 episode, alongside Karl Stefanovic, to raise awareness about breast cancer as she is a patron of the National Breast Cancer Foundation.

Screened in November 2009, Murdoch and her production company Room 329 Productions, along with Foxtel produced 4 episodes of Pride of Australia which was inspiring for fellow Australians and along with people from all over the world. With Murdoch as host, they tell the inspiring stories of everyday Australians, exhibiting acts of great courage, love and determination when faced with adversity. The stories were taken from thousands of people nominated to News Limited papers across Australia.

Murdoch replaced Jodhi Meares as host of Australia's Next Top Model after Meares infamously blundered her way through the third season's live finale in 2007 and flat-out refused to appear in 2008's finale. In addition to hosting Top Model, Murdoch also inked a deal with Foxtel to create documentaries with her production company, Room 329 Productions. She experienced media scrutiny during the 2010 Australia's Next Top Model Grand Final for announcing an incorrect winner. On 12 December 2011, Murdoch announced that she is leaving Top Model after three seasons.

Murdoch hosted the Network Ten reality dance programme Everybody Dance Now in August 2012, however due to poor ratings, the series was axed after just four episodes.