He left the sport after his last win, in 2005, only to return to the tour in 2009.
Armstrong still insists he was clean when he finished third that year, but that comeback led to his downfall.
"We wouldn't be sitting here if I didn't come back," he told Winfrey.
In 2011, Armstrong retired once more from cycling. But his fight to maintain his clean reputation continued. Federal prosecutors launched a criminal investigation, but it was dropped in February.
In April, the USADA notified Armstrong of an investigation into new doping charges. In response, the cyclist accused the organization of trying to "dredge up discredited" allegations and filed a lawsuit in federal court trying to halt the case.
Those who suffered for speaking out now feel vindicated.
They include Betsy Andreu, wife of fellow cyclist Frankie Andreu, who said she overheard Armstrong acknowledge to a doctor treating him for cancer in 1996 that he had used performance-enhancing drugs.
"This was a guy who used to be my friend, who decimated me," Andreu told CNN's Anderson Cooper on Thursday night. "He could have come clean. He owed it to me. He owes it to the sport that he destroyed."
The former athletic icon conceded he'd let down many fans "who believed in me and supported me."
"I will spend the rest of my life ... trying to earn back trust and apologize to people."