The Duchess of Sussex has begun legal action against the Mail on Sunday over a claim that she unlawfully published one of her private letters.
In a statement, the Duke of Sussex said he and Meghan were forced to take action against "relentless propaganda".
Prince Harry said: "I lost my mother and now I watch my wife fall victim to the same powerful forces."
A Mail on Sunday spokesman said the paper stood by the story it published and would defend the case "vigorously".
Law firm Schillings, acting for the Duchess, accused the paper of false campaigning, derogatory stories.
The firm has filed a High Court lawsuit against the paper and its parent company over alleged misuse of private information, copyright infringement and breach of the Data Protection Act 2018.
In a lengthy personal statement on the Duke and Duchess of Sussex's official website, Prince Harry said the "painful" impact of the intrusive media coverage had driven the couple to take action.
Referring to his late mother Diana, Princess of Wales, the prince said his "deepest fear is history repeating itself".
"I've seen what happens when someone I love is commoditized to the point that they are no longer treated or seen as a real person," he said.
BBC royal correspondent Nicholas Witchell said the statement was "remarkably outspoken" and "nothing less than a stinging attack on British tabloid media".
It is not the first time the royals have taken legal action against the press. In 2017, the Duke and Duchess of Cambridge were awarded £ 92,000 (100,000 euros) in damages after the French magazine Closer printed topless pictures of the duchess in 2012.
A French court ruled the images had been an invasion of the couple's privacy.
'Lie after lie'
The new legal proceedings are privately funded by the couple and any proceeds will be donated to an anti-bullying charity.
In his statement, Prince Harry said he and Meghan believed in "media freedom and objective, truthful reporting" as a "cornerstone of democracy".
But he said his wife had become "one of the latest victims of a British tabloid press that wages campaigns against individuals with no thought of consequences – a ruthless campaign that escalated over the past year, throughout her pregnancy and while raising our newborn son. ".
Prince Harry said: "There is a human cost to this relentless propaganda, especially when it is knowingly false and malicious, and though we have continued to put on a brave face – as so many you can relate to – I cannot begin to describe how painful it has been. "
He said "positive" coverage of the couple's current tour of Africa had exposed the "double standards" of "this specific press pack that has been vilified almost daily for the past nine months".
"They have been able to create lie after lie at her expense simply because she has not been visible while on maternity leave," he said.
"She's the same woman she was on our wedding day a year ago, just as she's the same woman you've seen on this Africa tour."
'It is bullying'
The duke said he had been a "silent witness to her private suffering for too long".
"To stand back and do nothing would be contrary to everything we believe," he said.
He accused the paper of misleading readers when he published the private letter, by strategically omitting paragraphs, sentences and specific words "to mask the lies they had perpetrated for over a year".
"Put simply, it's bullying, which scares and silences people. We all know this is not acceptable, at any level," he said.
"We cannot and cannot believe in a world where there is no accountability for this."
The Mail on Sunday spokesperson said: "We categorically deny that the Duchess's letter was edited in any way that changed its meaning."