Her father is Jonathan Guinness, 3rd Baron Moyne, the eldest son of Diana Mitford and Bryan Guinness. Diana Mitford was the daughter of David Freeman-Mitford, 2nd Baron Redesdale, the father of the Mitford sisters. Mitford divorced Guinness and married the leader of the British Union of Fascists, Sir Oswald Mosley, 6th Baronet of Ancoats. Daphne Guinness has said she did not know of Mosley’s political affiliations, before she heard in 1980 on the BBC News that he had died.

In 1985, when she moved to New York City, Guinness came to know Andy Warhol, for whom her sister Catherine had been a personal assistant for many years. In 1987, she married Spyros Niarchos, the second son of Stavros Niarchos, the shipping magnate. The couple had three children. Her $39 million settlement, obtained at the time of her 1999 divorce, was added to her Guinness inheritance.

Guinness has walked in two of Naomi Campbell’s Fashion for Relief shows to raise funds for disaster victims. In the same vein, in April 2008, she auctioned off part of her wardrobe, with the proceeds going to a struggling British charity called Womankind Worldwide, which deals with women’s issues at home and abroad, such as domestic violence.

In Spring 2009 Guinness was chosen as the face of an advertising campaign for Swiss clothing brand Akris. In 2009 Guinness launched her eponymous fragrance in partnership with French fashion house Comme des Garcons.

She designs fashion, jewellery, and perfume. Since 1994, she has been on the International Best Dressed List. In 2010, she was named in Tatler’s top 10 best-dressed list. In 2011, she created a make-up line for MAC cosmetics.

In June 2010, Guinness purchased at auction the entire wardrobe of Isabella Blow, her friend who committed suicide in 2007. The lot was purchased prior to an auction which was arranged at Christie’s. Guinness said of the purchase, “Indeed, in many ways, the auction would not be merely a sale of clothes; it would be a sale of what was left of Issie, and the carrion crows would gather and take away her essence forever.” She later announced that she would be displaying the wardrobe at Central Saint Martins and online, as well as starting a foundation to help with mental illness. The official show, entitled “Isabella Blow: Fashion Galore,” is set for display in November 2013 at Somerset House in London.

In Autumn 2010 Guinness launched a limited edition makeup line with French cosmetics company NARS. In 2011 Guinness collaborated with MAC cosmetics to launch a limited edition makeup line.

In September 2011, more than half a million visitors attended the Alexander McQueen exhibition “Savage Beauty”, at the Metropolitan Museum of Art in New York. Shortly thereafter, the Museum at the Fashion Institute of Technology devoted one of its galleries to about a hundred of Guinness’ most important pieces.

In May 2011 Guinness was asked to dress live in the window of department store Barney’s New York ahead of the Costume Institute’s MET Gala, to mark the opening of “Savage Beauty”.

In 2011 Guinness was photographed by photographer Bryan Adams and featured on the cover of Zoo Magazine.

In 2011, Guinness starred in Joe Lally’s film, “The Murder of Jean Seberg”.

In December 2011, she was photographed, while recorded livestream, by Nick Knight of SHOWstudio.com for 36 hours, resulting in five short films which were played in the windows of the Paris department store, Printemps. In several of these films, Guinness, a soprano, sang opera arias, making her public musical debut.

In 2012, Guinness auctioned 100 items from her wardrobe to raise funds to start the Isabella Blow Foundation: a charity that provides donations for bursaries at Central Saint Martins School of Art and Design, and also supports mental health charities.

On 31 January 2012, Guinness had put her art-filled Fifth Avenue apartment for sale for 14 million US dollars.

In 2012, Guinness starred in Shakki, a short sci-fi fiction directed by Julien Landais.

In February 2013 Guinness, along with Baroness Monica von Neumann and Lynn Ban, donated a collection of her shoes to the Museum at Fashion Institute of Technology’s Shoe Obsession exhibit.

In 2016 Guinness starred in Stevn Klein’s advertising campaign for Macallan Whiskey. Guinness appears extensively in David La Chapelle’s 2017 ‘Lost And Found’ series.

In 2017 Guinness starred in ‘The Aspern Papers’, a film inspired by letters between romantic poet Jeffrey Aspern and Juliana Bordereau directed by Julien Landais.

In 2017, Guinness auctioned Contra Mundum, a gold and diamond set chainmail glove made in partnership with jewellery designer Shaun Leane, through Sotheby’s NYC. It sold for an undisclosed sum.