In 1794, Elizabeth married William Seton, and they were blessed with five children. During their trip to Livorno, Italy, in 1803, William died. Catholic friends displayed such great kindness to her that she became interested in their faith. In 1805, despite strong opposition from her Episcopalian friends, she became Catholic. Three years later, she opened a school in Baltimore.
The following year, she established in Emmitsburg, Maryland, the first house of what later grew into the Congregation of the Sisters of Charity of St. Joseph. Elected the first superior of the order, she held that office until her death in 1821. The Sisters of Charity, whose rule was modeled upon that of the Daughter of Charity of St. Vincent de Paul, laid the foundation for the parochial school system in America.