Josephine Le Monnier was the daughter of a wealthy businessman and was educated largely in Europe. After the death of her mother in 1831 and the decline of the family's fortune shortly thereafter, she lived with her father and sister in New Orleans, Louisiana. In 1845 she married Warren Newcomb, a prosperous wholesale grocer of Louisville, Kentucky. For some years they lived by turns in New Orleans, Louisville, and New York City. Her husband retired from active business in 1863 so that they might devote themselves to the rearing and education of their daughter, Harriott Sophie. He died three years later, leaving a fortune to Josephine and Sophie. Sophie died of diphtheria in 1870, and after a period of despondency Newcomb set about finding a suitable memorial for her.

Astute business sense enabled Newcomb to increase her wealth, and she made sizable donations to Washington and Lee University in Lexington, Virginia, to the Confederate Orphan Home in Charleston, South Carolina, and to other institutions. In October 1886, at the suggestion of an old friend, she gave $100,000 to the newly established Tulane University in New Orleans for the creation of the H. Sophie Newcomb Memorial College for women. Newcomb College opened in September 1887 and proved a success as the nation's first self-sufficient women's college connected with a men's college. Over the next several years Newcomb's gifts to the college totaled about $1 million. Upon her death in 1901, her will, with a bequest that amounted to about $2.5 million, named Newcomb College residuary legatee.