In 1968 Donna took up a summer job with the designer Anne Klein. Karan's talent drew the attention of Patti Cappalli head of a label called "Addenda" and it was under her tutelage that Donna Karan developed as a designer. Karan worked with Cappalli for 18 months.

In 1970 Donna Karan returned to Anne Klein. In 1974 Anne Klein died of cancer, and Donna Karan completed her unfinished collection. Donna Karan and her Parsons classmate Dell 'Olio made Anne Klein into one of the biggest and most profitable designer sportswear companies in the USA.

She collected 3 Coty Awards (The American Fashion Designer's version of the Oscar) during the time she was with Anne Klein.

In 1985 Donna Karan went solo, and started her own label, the Donna Karan Collection. In 1988 she started a second line which she called DKNY (Donna Karan New York) Her collection was of co-ordinated working outfits, which could mix-and-match, along with a range of accessories to complement her designs. She combined comfort and simplicity with elegance to make sportswear, working wear and evening dresses. Her designs were considered classics.