The episode premieres Monday, Sept. 14 (check local listings), following the release of Houston's much-anticipated new album, I Look to You, on Aug. 31.
Winfrey described the exclusive as "the most anticipated music interview of the decade."
Houston, cited by the Guinness Book of World Records as the "most awarded female artist of all time" with 411 awards since her self-titled debut in 1985, has also starred in several movies, including The Bodyguard with Kevin Costner.
Fans noted a change in the pop diva's behavior and appearance as she became the tabloid target because of her troubled marriage to singer Bobby Brown.
In her last interview, almost seven years ago, Houston sat down one-on-one with Diane Sawyer and spoke out about ongoing drug rumors.
"First of all, let's get one thing straight. Crack is cheap," Houston told Sawyer. "I make too much money to ever smoke crack. Let's get that straight. Okay? We don't do crack. We don't do that. Crack is wack."
Watch Houston say the now-famous line in the interview below: