Having been trained in ballet at the Beijing Dance Academy, Liu Shishi made her acting debut in the television drama series The Moon and the Wind (2005). She included a segment of Swan Lake in one of her scenes. She then starred in The Young Warriors (2006) and The Fairies of Liaozhai (2007).

In 2007, Liu graduated from Beijing Dance Academy and was signed on by Tangren Media, successfully making her transition from a Dancer to an Actress. She then starred as Mu Nianci in The Legend of the Condor Heroes (2008), which gained her more recognition.

Liu gained popularity after appearing in the popular xianxia drama Chinese Paladin 3 (2009); her role as Long Kui broke her previous typecasting as a "gentle, kind, and understanding maiden" and received positive reviews from critics and fans.

The following year, Liu was cast in the drama A Weaver on the Horizon (2010), based on the life story of Huang Daopo. Originally cast in the role of the lead female protagonist, Liu instead chose to portray the Princess Zhao Jiayi, as she felt that the character's developments would challenge her acting.

The year 2011 saw Liu's further rise in popularity with two successful dramas. She starred alongside Wallace Huo in period action drama The Vigilantes In Masks, which was a ratings success and led to increased popularity for Liu. She then played the female protagonist, Ruoxi in the time travel series, Scarlet Heart, based on the novel Bu Bu Jing Xin by Tong Hua. The drama became a major sleeper hit in China, and swiftly gained popularity across East Asia. Liu, then a rising Actress, was propelled to stardom. Liu bagged several awards at local award-giving bodies for her performance, including Most Popular Actress awards at the China TV Drama Awards and Shanghai Television Festival.

In 2012, Liu starred in Xuan-Yuan Sword: Scar of Sky, adapted from the video game of the same name. The fantasy-action drama topped TV ratings and garnered 2 billion views online, becoming the 9th drama in Hunan TV's broadcast history to achieve that feat. Liu's soaring popularity due to Scarlet Heart in 2011 coupled with Xuan-Yuan Sword: Scar of Sky in 2012 allowed her to become the "Golden Eagle Goddess" at the 9th China Golden Eagle TV Art Festival. Liu was also chosen by Southern Metropolis Daily as one of the new Four Dan Actresses alongside AngelaBaby, Yang Mi and Ni Ni.

In 2013, Liu starred in action comedy Badges of Fury alongside Jet Li. She then starred in wuxia film Brotherhood of Blades, alongside Taiwanese actor Chang Chen, which received critical acclaim acclaim. Liu was nominated for Best Actress at the China Film Directors' Guild Awards for her performance.

Liu registered her marriage with Scarlet Heart co-star Nicky Wu on January 20, 2015 and the wedding ceremony was held in Bali, Indonesia on March 20, 2016.

Liu then headlined The Imperial Doctress (2016), based on the history of Tan Yunxian, a famous female physician during China's Ming Dynasty. The drama was extremely popular during its run, and Liu won the Most Influential Actress award at 1st China Television Drama Quality Ceremony for her performance.

In 2017, Liu starred along veteran actors Wang Qianyuan and Cao Bingkun in the spy drama, The Battle at Dawn; produced by the Ministry of Public Security. The same year, she played a young single mother in romance melodrama Angelo alongside Ming Dao. Liu then starred in historical fantasy drama Lost Love in Times alongside william Chan, as well as the crime suspense film The Liquidator.

She returned to the small screen with historical drama Sound of the Desert, based on the novel Ballad of the Desert written by Tong Hua. The series gained high ratings domestically, and was also well-received overseas. Liu then starred in romance film Five Minutes to Tomorrow. She and co-stars Haruma Miura and Joseph Chang attended the 19th Busan International Film Festival for the premiere of the film, where she received the Asia Star Award.