Zhou achieved breakthrough on the big screen with Lou Ye's Suzhou River (2000), which won her the Best Actress award at the 15th Festival du Film de Paris. That year, she was named one of the Four Dan Actresses alongside Zhang Ziyi, Zhao Wei and Xu Jinglei. She further achieved international recognition when she starred in the Franco-Chinese romance drama film Balzac and the Little Chinese Seamstress (2002).

Zhou impressed critics once again with her performance in Peter Chan's musical film Perhaps Love (2005). The film represented Hong Kong at the 2006 Academy Awards. Zhou received Best Actress awards at the Hong Kong Film Awards, Hong Kong Film Critics Society Award, Golden Bauhinia Awards and Golden Horse Awards. She next starred in Feng Xiaogang's wuxia film The Banquet (2006), inspired from william Shakespeare's Hamlet. Zhou plays the girlfriend of the crown Prince, equivalent to Ophelia. She won the Golden Bauhinia Awards and Hong Kong Film Awards for Best Supporting Actress. In 2007, she starred in Susie Au's film Ming Ming, which was highly praised at the 11th Pusan International Film Festival. Zhou played dual roles - twins with absolutely different characteristics and personalities.

Zhou Xun was named the first United Nations Development Programme (UNDP) Goodwill Ambassador for China in 2008 with a special focus of promoting environmental sustainability. Zhou jointly runs a campaign 'Our Part', which promotes ‘tips for green living’.

In 2009, Zhou was named the Star of the Year at CineAsia exhibition and distribution convention in Hong Kong. Asia-Pacific Producers Network (APN) also honored her as the Asian Star of the Year for her exemplary box office achievements. In an interview with CNN, Zhou was named Asia's 25 greatest actors of all time.

In 2010, she became the Laureate of United Nations Environment Programme (UNEP)'s Champions of the Earth (Inspiration & Action). She was the first entertainer in the world to receive this honour. She was also the Green Ambassador for the 2010 World Expo in Shanghai.

Since 2011, Zhou was formally announced as a new ambassador for Chanel. Chanel chief designer Karl Lagerfeld noted Zhou Xun for her strong fashion sense, describing the Actress as "a synthesis of young Coco Chanel and Ballet Troupe Zizi Jeanmaire."

In 2012, Zhou made her Hollywood debut in the science fiction film Cloud Atlas, playing multiple roles in the film. Zhou then reprised her role in Painted Skin: The Resurrection (2012), the sequel to Painted Skin. The film grossed over the 700 million yuan ($109.8 million) landmark, becoming the highest-grossing Chinese-language movie of all time then.

Zhou Xun married American actor Archie Kao on July 16, 2014 on stage after a charity event in Hangzhou, China.

In 2015, Zhou served as a jury for the 5th Beijing International Film Festival. Zhou returned to the screen in 2017, starring in war film Our Time Will Come directed by Ann Hui. The same year, she will also star in historical drama Ruyi's Royal Love in the Palace.