In 1889, Bishop O’Connor agreed Katharine was called to be a religious, but in spite of her preference for a cloistered life, he urged her to found a congregation to work with the Black and Indian peoples. She hesitated, but, after taking it to prayer, accepted this as her vocation. She pronounced her vows as the first Sister of the Blessed Sacrament on February 12, 1891.

She and 13 companions moved into St. Elizabeth Convent in Bensalem in 1892. On the property, they had erected a boarding school for black children that was connected to the chapel by a covered walk. By 1894, young Sisters of the Blessed Sacrament were in St. Catherine Indian School in Santa Fe; in St. Francis de Sales School in Virginia in 1899; and in 1902, in St. Michael Indian School on the Navajo Reservation in Arizona. Gradually other boarding schools sprang up on reservations. In day schools the Sisters taught elementary and high school levels in urban and rural areas of the Northeast, the Midwest, the Southwest and the South.

In 1917, a school to prepare teachers was established in New Orleans. By 1925, it received a charter as Xavier University of Louisiana. A severe heart attack in 1935 curtailed Saint Katharine’s missionary travels. Although for about 20 years she lived in prayerful retirement, her love and interest in the missions continued until her death on March 3, 1955. Saint Katharine was the last of the three Drexel sisters to die. The estate of Francis A. Drexel then was distributed to the charities listed in his will.