William's astonishing rebuke to the public broadcaster comes after a report published Thursday said the inquiry found that BBC journalist Martin Bashir used deceit to win a sensational 1995 interview with Diana, and that the broadcaster covered up the deception.
During the "Panorama" interview, watched by more than 20 million viewers in Britain, Diana shocked the nation by admitting to an affair and sharing details of her marriage to the heir to the throne and William's father, Prince Charles.
Diana died in a Paris car crash in 1997 at the age of 36.
"It is my view that the deceitful way the interview was obtained substantially influenced what my mother said. The interview was a major contribution to making my parents' relationship worse and has since hurt countless others," William, 38, said in a statement.
"It brings indescribable sadness to know that the BBC's failures contributed significantly to her fear, paranoia and isolation that I remember from those final years with her."
In a separate statement issued at the same time, William's brother Harry did not mention the BBC by name, but drew broader aim at the media and the "ripple effect of a culture of exploitation and unethical practices (which) ultimately took her life."