After working as a handbag designer for other companies, Leiber founded her own business in 1963. She is known for her crystal minaudières, evening purses made of a metal shell often encrusted with Swarovski crystals, plated with silver or gold and with various forms, such as baby pigs, slices of watermelon, cupcakes, peacocks, penguins, and snakes. Sold at exclusive boutiques around the world, her purses may cost up to several thousand dollars and have become a status symbol for many women, including several Presidential First Ladies to whom she has given them as a present, from Mamie Eisenhower to Barbara Bush and Hillary Clinton. Animals are a recurring theme in her designs, and often ornament the most expensive purses of the collection, with prices on some animal-shaped minaudières exceeding US$7,000. Some wealthy women collect them; Bernice Norman, an arts patron in New Orleans, owns close to 300 of the Leiber bags.

In 1994, Leiber received a Lifetime Achievement Award from the Council of Fashion Designers. She retired in 1998. In September 2008, she was rated the most prestigious luxury handbag brand for the second year running by the New York-based Luxury Institute. In 2010, Leiber received a Visionary Woman Award from Moore College of Art & Design. Examples of her work can be found in the permanent collections of the Smithsonian Institution in Washington, DC, the Metropolitan Museum of Art in New York City, and the Victoria and Albert Museum in London. The Taubman Museum of Art in Roanoke, Virginia, has had a gallery of her work on display since it opened in 2008.

The Leibers bought property in Springs, New York in 1956 and it became their primary residence in 2011. In 2005 they opened the Leiber Museum across the street from their home to display the bags as well as paintings by Gerson Leiber. The Leibers sought to buy back an example of all of the purses to be displayed at the museum. The museum also displays various awards including the 1973 Coty Award.