2010: OST

In 2010, Yesung starred in the title role of musical Hong Gil Dong, alongside band mate Sungmin who also played the historical figure Hong Gildong. It played at the Woori Financial Art Hall at the Olympic Park from 18 February to 18 April 2010. On 31 March 2010, Yesung contributed to the OST of television drama Cinderella's Sister, starring Moon Geun-young and Chun Jung-myung. The song, "It Has To Be You", is a ballad that tells the story about a man who refused to look for another girl, except for the one he loved. On 4 June, Yesung performed it for the first time, and his first solo stage, on Music Bank which reached #3 on show's K-Chart.

In July 2010, Yesung appeared with band mate Leeteuk as MC's for MBC's Love Pursuer. The show presents a Korean celebrity being showered with affection from a secret admirer, with the challenge of guessing who the admirer is. Yesung was himself the subject of admiration in episode 10. During the recording of Dream Team 2 on 21 August 2011, he fell from a platform and strained his waist again, but was reported to be a minor injury. On 4 September, he became the new MC for MUZIT, a musical talk show alongside K.Will and veteran composer Yoo Youngsuk. It showcased various musical talents from the Korean music industry.

From 1 October to 28 October 2010, also he starred in his third musical Spamalot playing the main role of Sir Galahad.

On 29 December 2010, Yesung together with Luna of f(x), sang the track "Loving You", on part two of the original soundtrack of KBS drama President.