Weymouth grew up on the Upper East Side of Manhattan, New York City and attended The Brearley School, Harvard College/Radcliffe College, Oxford University, and Stanford Law School.
While an associate at Williams & Connolly, a prominent law firm in Washington, D.C., Weymouth went to work as an assistant counsel of the Post in 1996. She later became the head of advertising. Weymouth was named publisher of the Post and chief executive officer of Washington Post Media on 7 February 2008, succeeding Boisfeuillet Jones, Jr.
Among her first actions as publisher was hiring Marcus Brauchli as executive editor and placing him in charge of both newspaper and the website (the previous editor had not been in charge of the website). The hire from outside the organization "surprised the newsroom. ... Brauchli ... had accepted a large payout and resigned from his previous job, running The Wall Street Journal under its new owner, Rupert Murdoch", as a 2012 Times account put it. The 2012 account outlined signs and reports that more recently her relationship with Brauchli may have "cooled" and noted that Raju Narisetti, whom Brauchli had brought with him from the Journal as a close partner "in the digital reinvention of the newsroom", had left the Post in January. However, the Times also said that "[b]y one important measure, The Post’s efforts are paying off. Recently, it has averaged 19.6 million unique visitors a month, according to comScore, making it the second-most-visited American newspaper Web site, behind that of The New York Times."
On July 3, 2009, The Politico website uncovered the story that Weymouth had planned a series of exclusive dinner parties or "salons" at her private residence, to which she had invited prominent lobbyists, trade group members, politicians and business people. The cost of attendance to the parties was up to $250,000 per individual, with the events being closed to the press and the public. Politico's revelation sparked controversy in Washington, as it gave the impression the parties' sole purpose was to allow a select group of Washington insiders and business people to purchase face time with Post reporters.
Almost immediately following the story, Weymouth cancelled the salons and blamed the entire incident on the Post's marketing department. The backlash also prompted David G. Bradley, publisher of The Atlantic, to admit that he hosts similar off-the-record discussions at his home and office at the Watergate, and in 2012, looking back on the incident, the Times said that "magazines host similar conferences all the time". However, it is unheard of to charge as much as $250,000 per person (if anything at all) for such an event.
On September 2, 2014, it was announced that she would resign as publisher the following month, with the position to be assumed by Politico's founding CEO Fred Ryan.
In 2015, DC tech startup FiscalNote announced that Weymouth would serve as an advisor to the company.
A granddaughter and namesake of long-time Washington Post chairwoman and publisher Katharine Graham (d. 2001), Weymouth is a daughter of political columnist and publishing heiress Lally Weymouth and the architect Yann R. Weymouth. Her mother's family owned the newspaper from 1933, when it was purchased by her great-grandfather Eugene Meyer, until it was sold to Jeff Bezos in 2013. Weymouth is the fifth member of her family to have held the publisher position.
On her father's side Weymouth is a niece of Tina Weymouth, a former member of the band Talking Heads. Her paternal grandfather is Admiral Ralph Weymouth. One of her ancestors is the Breton writer Anatole Le Braz.
Weymouth married lawyer Richard Alan Scully on 25 July 1998. The couple had three children, Madeleine, Beckett, and Bridget, and later divorced.