Born in Harvey, Illinois, she grew up listening to Aretha Franklin, Al Green, Tina Turner, the Dells, and Mavis Staples. She performed in local bands and sang in her church choir at Greater Christian Unity, and later worked in classical and gospel choirs as well as in jazz ensembles at Drake University and Illinois State University, where she majored in music.

Johnson's soulful rasp, reminiscent of old-school R&B singers, set the tone for her confessional songs. Her first recordings appeared on a 1995 album of duets with her father, but she made her proper debut in 1999 with Love Hangover, which featured covers of Diana Ross' "Love Hangover" and Womack & Womack's "Baby I'm Scared of You." She then signed with the Jive label for three albums, all of which reached the Top 20 of Billboard's R&B/Hip-Hop albums chart. On Chapter 1: Love, Pain & Forgiveness (2001), Johnson confronted her romantic pitfalls and coming of age with guest appearances by Buddy Guy and R. Kelly. Between Chapter 2: The Voice (2002) and Chapter 3: The Flesh (2005), she appeared on fellow Chicago native Kanye West's Grammy-nominated Top Ten Hot 100 hit "All Falls Down." Surprisingly, sales of the latter seemingly weren't increased by the single's success. In 2008, Johnson's Jive era was anthologized by I Am Your Woman: The Best of Syleena Johnson.

Johnson went independent for Chapter 4: Labor Pains (2009) and aligned with Lalah Hathaway, Indira Khan, and Simone and toured as Daughters of Soul. Chapter 5: Underrated, supported by a deal with the Shanachie label, followed in 2011. She co-starred in TV One's R&B Divas: Atlanta and appeared with some of her fellow reality stars' R&B Divas album. In 2013, she collaborated with Musiq Soulchild and producer Kemar McGregor for 9ine, a set of contemporary reggae duets. The following year, while signed to the Blakbyrd label, Johnson released Chapter 6: Couples Therapy, for which she worked extensively with Pierre Medor and Kriss Johnson. ~ Robert Hicks & Andy Kellman