During his third year of study at the Central Academy of Drama in Beijing, Deng achieved recognition from his performance in stage plays Cui Hua, Serve Suancai and Please. After graduation, he started filming dramas. He rose to fame with the 2003 historical television series The Young Emperor and further achieved recognition in Director Gao Xixi's military drama romance Happiness as Flowers, which marked his image transformation.

Deng is married to Actress Sun Li since 2010. They have two children, a son named Deng Han Zhi and a daughter named Deng Han Yi.

In 2013, Deng starred as one of the three male leads in Peter Chan's film American Dreams in China, about three young men from poor backgrounds who achieved success by establishing a reputable English teaching school. The film was a commercial success and earned positive reviews. Taipei Times call the movie a "a well-executed work of entertainment that preaches about China’s growing power" and praised Deng for "delivering a focused performance as an idealist with a defeated ego".

Deng made his directorial debut with The Breakup Guru (2014), a romantic comedy starring himself and Yang Mi. Though it faced stiff competition from Hollywood blockbusters, the film grossed 180 million yuan in its opening week and ended up as one of the highest-grossing films in China that year. The same year, he joined Keep Running, a remake of the South Korean variety program Running Man. Keep Running enjoyed explosive popularity in China. That year, Deng was chosen as the Most Valuable Chinese Actor.

Deng then starred in crime film The Dead End directed by acclaimed Director Cao Baoping, and was praised by critics for "breathing life into the role with riveting performances", as well as his chemistry with co-star Duan Yihong. He shared the Best Actor award with co-stars Duan and Guo Tao at the 18th Shanghai International Film Festival, and won another Best Actor trophy at the Golden Rooster Awards. Deng teamed up again with Yu Baimei for the comedy film Devil and Angel, following the success of The Breakup Guru. However, unlike its predecessor, the film was voted the Most Disappointing Film of 2015 and received criticism for its poor approach to comedy.

In 2016, Deng and long-time partner Yu Baimei (who co-directed The Breakup Guru and Devil and Angel) set up their own theater, the Super Theater.

In 2017, Deng starred in Han Han's comedy film Duckweed, playing a rebellious car racer who thinks that his parents misunderstood him. The sleeper hit gained commercial and critical success. He next starred in the suspense crime film, The Liquidator, based on the bestselling crime novel series Evil Minds: City Light and directed by acclaimed TV Director Xu Jizhou.