Reese, a Christian, began singing at the age of six. She would later join famous gospel singer Mahalia Jackson as a back-up singer. While a student at Wayne State University she formed and performed with a gospel group, the Meditation Singers. Reese left university after her mother died and when her father developed serious health problems. While continuing to perform with the Meditation Singers she also performed in night clubs, notably the famous Flame Showbar, where as both a hostess and singer she heard some of the premier jazz artists of the day. She had by then married Vermont Taliaferro, and her married name was too long to fit on marquees, so she adopted a modification of her first name as a stage name.

In 1953, after signing with a New York City agent, she joined the Erskine Hawkins orchestra, and a year later signed a recording contract with Jubilee Records. Her biggest hits for Jubilee, both million-sellers, were "And That Reminds Me" and "Don't You Know." Her success on record led to a successful performing career, including nine years performing in Las Vegas.

In 1969, she was given her first shot at television stardom, when she starred on a self-titled variety series. A year later (after her variety series was canceled after one season), she became the first black woman to serve as guest host of The Tonight Show Starring Johnny Carson.

Reese later appeared in several TV movies and miniseries' (including The House of Yes, Sanford and Son (in Season 5 episode "Della Della Della" that featured her performing "Ease On Down the Road" with Redd Foxx), and Roots: The Next Generations) and was a regular on Chico and the Man. In 1979, after taping a guest spot for The Tonight Show, she suffered a nearly fatal brain aneurysm, but made a full recovery after two operations by noted neurosurgeon Dr. Charles Drake at University Hospital in London, Ontario. This was Reese's second brush with death. A number of years earlier, she accidentally walked into a plate glass door in her home. She was sliced so badly by the broken glass she required a thousand stiches to close her wounds. She lost most of her blood and later said she had a "near death" experience where she saw her beloved mother.

After appearing on two sitcoms, Reese did a voice over for the animated series A Pup Named Scooby-Doo. In 1989, she starred alongside Eddie Murphy, Richard Pryor and Arsenio Hall in the movie Harlem Nights. In 1991, she starred opposite Redd Foxx in his final sitcom, The Royal Family. His death halted production of the series for a few months.

From 1994 to 2003 Reese took on the role she is possibly best known for: Tess on the inspirational television drama Touched by an Angel. Reese also sang the show's theme song. Her participation in this series has given her popularity among the younger audiences a boost.

Della Reese announced, on Larry King's show in 2002, that she suffers from Type-2 Diabetes. She is a spokeswoman of the American Diabetes Association, travelling around the United States to raise awareness about the disease.

In 1983, she married Franklin Thomas Lett Jr., to whom she is still married. In 1987, she was nominated for an Grammy for one of her acclaimed gospel albums.