Armstrong, 41, who has already been stripped of his seven Tour de France titles and banned for life, is set to break his silence on the issue of using performance-enhancing drugs, according to the talk-show host.
The two-and-a-half hour interview, the first part of which is being aired in the early hours of Friday UK time, will see Armstrong address the accusations of years of cheating and lying about doping, according to Winfrey's website.
It was filmed in Armstrong's home city of Austin, Texas, on Monday. In the past week, Armstrong has made apologies to prominent figures in his sporting life and the Livestrong Foundation, the cancer charity he set up. In a tweet written after the interview, Winfrey wrote: "Just wrapped with @lancearmstrong More than 2 1/2 hours. He came READY!"
The motives for the confession remain unclear, but the Texan, who retired from cycling for a second time in 2010, was competing in triathlons until he was banned last year.
Armstrong's ban came after the United States Anti-Doping Agency found he had been at the heart of "the most sophisticated, professionalised and successful doping programme that sport has ever seen".
The World Anti-Doping Agency and the UCI, cycling's world governing body, have urged Armstrong to reveal all to the authorities if he is to have any hope of lifting his life ban.
The International Olympic Committee, meanwhile, is among those waiting for the interview to be broadcast before considering whether to demand that Armstrong returns the bronze medal he won in the road time-trial at the 2000 Games in Sydney.
In December, the IOC postponed a decision on whether to strip Armstrong of the medal because it had to wait until the UCI had declared all his results ineligible. If Armstrong does make a full confession in his interview with Winfrey, the IOC will ask for the medal to be returned.
The interview is being broadcast over two nights. The first part of the interview will be shown on The Oprah Winfrey Network at 9pm local time on Friday (2am GMT on Friday), with the second to follow 24 hours later. Both episodes are to be streamed live online.