Cabrini took religious vows in 1877 and added Xavier to her name to honor the Jesuit saint, Francis Xavier, the patron saint of missionary service. She became the Superior of the House of Providence orphanage in Codogno, where she taught, and drew a small community of women to live a religious way of life In 1880, the orphanage was closed and then opened again by her. She and six other women who had taken religious vows with her founded the Missionary Sisters of the Sacred Heart of Jesus (M.S.C.) on November 14.
Cabrini composed the Rule and Constitutions of the religious institute, and she continued as its Superior General until her death. The congregation established seven homes and a free school and nursery in its first five years. Its good works brought Mother Cabrini to the attention of (the now Blessed) Giovanni Scalabrini, Bishop of Piacenza, and of Pope Leo XIII.
Cabrini went to seek approval of the Pope to establish missions in China. Instead, he suggested to her that she go to the United States to help the Italian immigrants who were flooding to that nation in that era, mostly in great poverty. "Not to the East, but to the West" was his advice.
Cabrini followed the papal will and left for the United States, arriving in New York City on March 31, 1889 along with six other Sisters. There she obtained the permission of Archbishop Michael Corrigan, the Archbishop of New York, to found an orphanage, which is located in West Park, New York, today and is known as Saint Cabrini Home—the first of 67 institutions she founded: in New York, Chicago, Des Plaines, Seattle, New Orleans, Denver, Golden, Los Angeles, Philadelphia, and in countries throughout South America and Europe. Long after her death, the Missionary Sisters would achieve Mother Cabrini's goal of being missionaries to China. In only a short time, after much social and religious upheaval there, the Sisters left China and, subsequently, a Siberian placement.
In New York City, she founded Columbus Hospital and Italian Hospital. In the 1980s, they were merged into Cabrini Hospital. This facility was closed in 2002. In Chicago, the Sisters opened Columbus Extension Hospital (later renamed Saint Cabrini Hospital) in the heart of the city’s Italian neighborhood on the Near West Side. Both hospitals eventually closed near the end of the 20th century. Their foundress’ name lives on in Chicago's Cabrini Street.
Cabrini was naturalized as a United States citizen in 1909.
Mother Cabrini died of complications from dysentery at age 67 in Columbus Hospital in Chicago, Illinois, on December 22, 1917, while preparing Christmas candy for the local children. By that time, she had founded 67 missionary institutions to serve the sick and poor and train additional Sisters to carry on the work.
Cabrini's body was originally interred at Saint Cabrini Home, an orphanage she founded in West Park, Ulster County, New York.
In 1931, her body was exhumed as part of the canonization process, and was found to be partially incorrupt. The major portion of her body is now enshrined under glass in the altar at St. Frances Cabrini Shrine, part of Mother Cabrini High School, at 701 Fort Washington Avenue, in the Washington Heights section of Manhattan. At that time, her head was removed and is preserved in the chapel of the congregation's international motherhouse in Rome. The street to the west of the shrine was renamed Cabrini Boulevard in her honor.
Cabrini was canonized in Rome in 1946 by Pope Pius XII. Due to the overwhelming increase of pilgrims to her room at Chicago’s Columbus Hospital, the then-Archbishop of Chicago, Cardinal Stritch, consecrated a National Shrine built in her honor within the hospital complex.
The National Shrine of Saint Frances Xavier Cabrini was dedicated in 1955, 38 years after her death. Mother Cabrini lived, worked and died in Chicago so she is considered one of Chicago’s “Very Own”. It is located in the Lincoln Park area of Chicago at the former Columbus Hospital.