The Duchess of Sussex has begun legal action against the Mail on Sunday over a claim that it 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 falling 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 a campaign of false derogatory stories.
The firm has filed a High Court claim against the paper and its parent company over the alleged misuse of private information, infringement of copyright and breach of the Data Protection Act 2018.
The claim comes after the Mail on Sunday published a handwritten letter from Meghan to her father, Thomas Markle, sent shortly after she and Prince Harry got married in 2018.
In a lengthy personal statement on the Duke and Duchess of Sussex's official website, Prince Harry said the "painful" impact of 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 commoditised 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 the British tabloid media".
Former Daily Mirror editor and Guardian columnist Roy Greenslade said the duchess could win the legal action, but added Prince Harry had taken a risk by attacking the press for the actions of one newspaper.
"The press - particularly the tabloid press - is far less powerful now than it was during his mother's era," he told Radio 4's Today programme.
"Is he taking a sledgehammer to crack a nut here? I think he may well find that this is counter-productive."
The language is clearly Harry's: an unrestrained expression of anger and pain aimed at the British tabloid media.
Did any of his advisers urge restraint? We simply don't know. Judging by the length and intensity of the statement, Harry would have been in no mood to listen to any such cautionary advice.
Is it fair to castigate the entire British tabloid media off the back of one dispute with one newspaper over one story, however painful? That is a matter of individual opinion and clearly Harry - supported one assumes by Meghan - believes that it is.
The timing certainly is curious. They are concluding a visit to Southern Africa which by wide consent (much of it expressed in the tabloid media) has been a considerable success. It has lifted their reputation after a series of mis-steps involving private jets and expensive property renovations.
Now they have chosen to take one of the most powerful newspaper groups in Britain to court and launched this stinging assault on an entire section of the British media.
British tabloids are not afraid of a fight. They may well feel provoked by the language in this statement. Was it wise? We shall see.
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 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 being funded privately 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 to the consequences - a ruthless campaign that has 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, specifically when it is knowingly false and malicious, and though we have continued to put on a brave face - as so many of 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 vilified her 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 is the same woman she was a year ago on our wedding day, just as she is 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 in," he said.
He accused the paper of misleading readers when it 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 is bullying, which scares and silences people. We all know this isn't acceptable, at any level," he said.
"We won't and can't 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."