In 2011, Eunhyuk, along with Sungmin was placed two new members of Super Junior-M. On 27 September 2011, he along with Yesung and Shindong filled in for bandmate Heechul, who enlisted for mandatory military service on 1 September, during the performance on Music Bank and Show! Music Core of Kim Jang-hoon latest single, "Breakups are So Like Me". Heechul is featured in the song and starred in the music video, which was completed the day before he enlisted. Mr. Simple, Super Junior's award-winning 5th studio album, was promoted heavily with Eunhyuk participating in much of the album's production through choreography, and rap lyrics for the track, Oops. The album sold over 500,000 units and won the Disk Daesang Award at the 26th Golden Disk Awards and 21st Seoul Music Awards, as well as Album of the year at the 13th Mnet Asian Music Awards. The album is listed as the 2nd best-selling album as of the year 2011.
In November, Eunhyuk made his musical theatre debut in Fame, where he played Tyrone Jackson, along with Tiffany of Girls' Generation, Son Ho Young, Lina of The Grace and Kim Jung Mo of TRAX. It was on at the Woori Financial Art Hall from 25 November 2011 to 29 January 2012. It was announced on 30 November 2011 that after five years, he and Leeteuk would leave Super Junior's Kiss the Radio and was replaced by fellow members, Sungmin and Ryeowook on 4 December 2011.
On 16 December 2011 Eunhyuk and Donghae released digital single Oppa, Oppa, where they first performed it at Super Junior's Super Show 4 Seoul concert on 19 November 2011. This marks the first release of their collaborations. The single was also released in Japanese with an original Japanese music video on 4 April 2012. On the day of its release, it reached number two on Oricon Daily Chart with 42,114 copies sold. While also preparing for Super Junior's first world tour Super Show 4, the pair held a fan meeting, Premium Mini Live Event, in support of the single on 11 April at Shibuya-AX, Tokyo.