At the age of eleven or twelve, Staton and her sister Maggie were sent to the Jewell Christian Academy in Nashville, Tennessee. Her vocal abilities quickly set her apart from the crowd; the school's pastor teamed the two sisters with a third girl to form the Jewell Gospel Trio. As teenagers, they toured the traditional gospel circuit in the 1950s with The Soul Stirrers, C. L. Franklin, and Mahalia Jackson. They recorded several sides for Nashbro, Apollo, and Savoy Records between 1953 and 1963.

In 1968, Staton launched her solo career as a Southern soul stylist, garnering 16 R&B hits for Rick Hall's Fame Studios and gaining the title of "First Lady of Southern Soul" for her Grammy-nominated R&B renditions of the songs "Stand by Your Man" and "In the Ghetto". Staton appeared on the September 23, 1972 edition (Season 2, Episode 1) of Soul Train. In 1975, Staton began collaborating with producer David Crawford on disco songs such as "Young Hearts Run Free", which reached #2 in the UK Singles Chart,[4during the summer of 1976. It was remixed and re-released in 1986 reaching the UK Top 50. Follow up song "Destiny" hit the Top 50 in the UK. Candi's version of "Nights on Broadway" hit the UK Top 10 in 1977;it had been a US Billboard hit for the Bee Gees over a year before. In 1978 she scored another Top 50 hit in the UK with "Honest I Do I Love You". Other club hits included "When You Wake Up Tomorrow" and "Victim". In 1982 Candi again hit the UK chart with a version of Elvis Presley's "Suspicious Minds". In 1997, singer Kym Mazelle recorded "Young Hearts Run Free" for the film adaption of Romeo and Juliet. Staton collaborated with Change, Luther Vandross, and Janet Jackson on her 1979 album title song "Chance" and album single "When You Wake Up Tomorrow" (co-written by Patrick Adams and Wayne K. Garfield, lyricist).

In 1982, Staton returned to gospel music. She married her fourth husband, John Sussewell (drummer for Ashford & Simpson and also Dory Previn's sixth album). Together they founded Beracah Ministries in Atlanta, Georgia with help from Jim and Tammy Faye Bakker's PTL Ministries.She has since recorded

In 1991 she returned to popular mainstream charts by lending her vocals to The Source's Top Ten British hit, "You Got the Love," a club-styled dance hit that sold two million copies and that is still considered a seminal classic of that era, leading to many remixes and cover versions being created.Staton signed with Intersound Records in 1995. In 2000, she released her eleventh album, Here's a Blessing. In 2004, the British record label Honest Jon's released a compilation CD of her country-soul work from the late 1960s and early 1970s, the self-titled Candi Staton, and Staton followed it up with a secular project in 2006 entitled His Hands, produced by Mark Nevers of Lambchop and with the title track written by Will Oldham. Two of Staton's children, Cassandra Hightower (background vocals) and Marcus Williams (drums), joined her on the CD. A second studio album for Honest Jon's is due out in February 2009, titled Who's Hurting Now?.

Staton's television show New Direction airs on TBN. Staton has also made appearances on the Praise the Lord telecast with Paul Crouch and his wife Jan Crouch.