On April 11, 2019, IU made her film debut in the Netflix anthology series Persona. She portrayed different characters in each of the four short films which were written and directed by the critically acclaimed directors Lee Kyoung-mi, Yim Pil-sung, Jeon Go-woon and Kim Jong-kwan. It was the sixth most popular program on Netflix in Korea in 2019. During the summer, IU starred in the fantasy mystery drama Hotel del Luna, written by the Hong Sisters. She also sang one of the songs on the soundtrack, "Happy Ending". The drama was a commercial success, recording the highest ratings in its timeslot throughout its run.

IU was set to release her ninth extended play, Love Poem, on November 1, 2019; however, she decided to postpone the EP's release to November 18 following her close friend Sulli's death. Her single "Peach" (2012), inspired by Sulli, re-entered charts as a tribute to the late singer. The EP's eponymous lead single was released as planned, subsequently peaking at number one on the Gaon Digital Chart, and at number nine on Billboard's World Digital Songs Chart. On November 2, 2019, IU began her second Asian tour, titled Love Poem, in Gwangju. Nearly 90,000 fans attended her two-month tour during which she visited 10 cities.

For the first time in nine years, IU participated in a soundtrack album with the song "Give You My Heart" for the hit romantic comedy Crash Landing on You. Released on February 15, 2020, it debuted at number 71 on South Korea's Gaon Digital Chart, 2020,] rising and reaching number one the following week. On May 6, 2020, IU released the single "Eight" featuring and produced by BTS's Suga. As the song's title derives from the last digit of the Korean age "twenty-eight" of both artists, it follows IU's previous singles "Twenty-Three" (2015) and "Palette" (2017) which together comprise her "coming-of-age" series. On June 19, 2020, IU released the song "Into the I-LAND" as the signal song for the survival reality show I-Land.

On January 9, 2021, IU won Song of the Year at the 35th Golden Disc Awards for "Blueming", becoming the first female soloist to win two grand prizes in the award show's history. While onstage accepting her award, she hinted that she would be soon returning with a new single titled "Celebrity" and that the new song would have a refreshing and cheerful pop sound. Two days later, Edam Entertainment confirmed her return with the pre-release single "Celebrity" on January 27, 2021. On March 3, she announced her fifth studio album, Lilac, which was released on March 25 to immediate commercial success. The album debuted atop the Gaon Album Chart, and all tracks had simultaneously charted in the top 30 of the Gaon Digital Chart. In October, IU announced that her digital single "Strawberry Moon" would be released on October 19. IU later teased a special album titled Pieces, which was released on December 29.