The roots of St. Anthony Shrine can be traced to the arrival between 1728 and 1740 of several Catholic Families from southern Maryland - the Elders, the Livers, and the Owings. Through these families the immediate area was destined to become a focus for the Catholic religious in northern Frederick County. Jesuit missionaries, principally from Conewago, but later from Frederick town, provided the Sacraments on an irregular, itinerant basis.

In 1792, Fr. John DuBois was assigned by Bishop John Carroll to the pastoral duties of much of Central and Western Maryland. In 1805, he left Frederick and began the construction of St. Mary's Church (where the Pangborn Companile stands at the entrance to the Grotto of Lourdes on Mt. St. Mary's grounds). It is reported that the first Mass was said in that church on August 15th, 1906. DuBois subsequently (1808) established Mt. St. Mary's as a college and seminary. For the next 86 years, the College's priest-president was pastor of St. Mary's Church and its congregation.

In 1894, the college's responsibility for the congregation was surrendered and a separate parish with full ecclesiastical jurisdiction was created by the Archdiocese. Fr. John Manly was the first pastor of the new parish - St. Anthony Shrine. Ground was broken for the rectory, July 10, 1895, and the dedication of the new church took placed on October 26, 1897. Fr. Thomas Lyons succeeded Fr. Manly and was followed by Fr. George H. Tragesser and others. More recent pastors include Frs. Edward A. Sargus, Vincent Tomalski, William A. McEvoy, Edward B. Hemler, Leo R. Tittler and James W. Hannon.

In the fall of 1988, Fr. Donald Croghan, Pastor of Our Lady of Mount Carmel Church in Thurmont, was assigned as Pastor of St. Paul's Church, Ellicott City. Founded as a mission from Mt. St. Mary's in the 1850's, Mount Carmel became a mission of the newly formed St. Anthony Shrine and continued so until created an independent parish not long before 1920.

From November 1988 until March of 1989, Mount Carmel was without a pastor and was served on a voluntary basis by faculty priests from Mt. St. Mary's. In March, diocesan officials announced that Fr. Edward B. Hemler, Pastor of St. Anthony Shrine, would assume the joint pastorate of the two churches, assisted by Deacon Michael Lind. In February 1992, Fr. Leo R. Tittler was appointed to the joint pastorate and in 1993, Sr. Carol Czyzewski, F.S.S.J. replaced Deacon Lind as Pastoral Associate. In 1995 Sr. Mary Jan Nasaidka, F.S.S.J. joined the Staff as Pastoral Minister and served the parishes until 1998 at which time Sr. Valenta Rusin, F.S.S.J. replaced her and today also serves as Director of Religious Education. In January 2001, Fr. Leo Tittler was assigned as Senior Priest at St. John's in Frederick and Fr. James Hannon was appointed as pastor of St. Anthony Shrine and Our Lady of Mt. Carmel.

The cemetery which had been under the aegis of Mt. St. Mary's College was early transferred to the care of St. Anthony Shrine. Dating from 1806, the cemetery is a historic spot including as it does the graves of many local Catholic families as well as those of faculty and students of Mt. St. Mary's and several members of the family of St. Elizabeth Ann Seton.