Mainbocher was a native of Chicago, where he studied art at the University of Chicago and the Chicago Academy of Fine Arts. He served in the Army in the first World War and stayed on in Paris after the war, working as a fashion illustrator for Harpers Bazaar and later as a fashion editor for French Vogue.
In 1929, he established his own fashion house at 12 Avenue George V in Paris, designing expensive, elegant haute couture dresses and gowns for an exclusive clientele, and charging them for the privilege of viewing his collections. He designed much of the Duchess of Windsor's wardrobe, naming a color, Wallis blue, for her, and created the first strapless evening gown.
After he achieved fame for dressing some of the world's most famous women, Mainbocher was commissioned to design the costumes for Mary Martin in the 1943 Broadway musical One Touch of Venus and for Ethel Merman in the 1950 musical Call Me Madam. Merman recounts in her memoirs that she took her mother to her first fitting for her costumes. Mainbocher would not permit Merman's mother in the fitting area saying he did not allow outside persons in the areas where he created. When Merman inquired why he would not allow her mother when he allowed another old woman in the room, Mainbocher replied, "But that is my mother."
Recently, Mainbocher and twenty-three other American fashion designers were honored with bronze plaques on New York City's "Fashion Walk of Fame" in the legendary garment district.
Mainbocher was also the designer of the clothes worn by Mary Martin in the Broadway production of The Sound of Music, and for Lauren Bacall in Applause. Mainbocher was located at 609 Fifth Avenue prior to his retiring and closing his house.