The Guild of St. Apollonia was established on March 20, 1920, by 12 Catholic dentists in the Archdiocese of Boston. It was the first guild of Catholic dentists in the U.S., and was founded "to create an organization among Catholic dentists in the Archdiocese of Boston for the Advancement of its intellectual and moral interests; and to offer to Catholic Schools and institutions the opportunity of securing necessary dental attention," according to its constitution, found in the Chancery Files in the archives. St. Apollonia, a martyr from the third century, is the patron saint of dentistry and dental problems. Membership to the guild was available to male Catholic dentists who met professional ethical standards.

The guild partnered with the Forsyth Dental Infirmary, located on the Fenway in Boston, to provide dental care for children attending parochial schools in the archdiocese. They transported students by bus to and from the infirmary, where member dentists examined and treated students. The first infirmary bus was donated by Joseph P. Kennedy, former U.S. ambassador to Britain and a longtime benefactor of the guild. The guild sustained itself through fundraising, especially by appeals to the pastors of the parochial schools.

Cardinal O'Connell, who served as the honorary president of the guild while he was archbishop, was another major supporter, and gave $1,000 annually from the year it was founded. "In reading the work which this Guild has achieved since its inception, it is marvelous, almost staggering ... The idea has succeeded beyond my wildest dream," Cardinal O'Connell said of the organization's rapid success, according to their Third Annual Report from 1923. From 1922 to 1923, the guild treated 11,170 children at parochial schools in Boston, including extracting 11,598 teeth and issuing 5,528 "Forsyth Cards" indicating that a child's teeth were in perfect order. Beginning in the late 1920s, the guild claimed to examine every student in parochial schools in the archdiocese.

After its founding, the guild quickly grew in membership and activity, reaching around 500 members in 1945. Aside from their treatment of parochial students, members met for annual retreats and hosted panel discussions for dental professionals, featuring topics such as prosthetics and jaw surgery presented by lecturers from Boston hospitals and universities. In 1925, the guild erected a shrine to St. Apollonia at St. Cecilia's in Back Bay, the church where they held their annual Communion Breakfasts. The guild also published a quarterly magazine, "the Apollonian," beginning in 1926, though printing was discontinued during World War II. In 1929, a National Guild of St. Apollonia was organized at the National Dental Association convention, for which Cardinal O'Connell also served as honorary president.

In 1929, Cardinal O'Connell petitioned the Apostolic Penitentiary to grant the privilege of special plenary and partial indulgences to members of the Guild of St. Apollonia. A plenary indulgence could be gained by members on the Sunday within the octave of St. Apollonia, and by attending at least five sermons or conferences at the guild's annual retreat. With Cardinal O'Connell's support, which included donating a new bus in 1940, the guild thrived, and provided dental care to hundreds of thousands of parochial school students. In 1945, to celebrate the silver jubilee, the guild gave five full scholarships to the Forsyth Training School for Dental Hygienists, available to Catholic girls over 18 who graduated from high school having studied at least one year of Latin, French, English, chemistry, and physiology.

However, after the 1940s, the work and reputation of the guild seemed to dwindle. The archbishop's office surveyed pastors in 1951 about the quality of work completed by the guild, with many parishes responding that they had never received any services or that the examinations were cursory and students received care elsewhere. Despite the poor reviews, Cardinal Cushing, who had assumed Cardinal O'Connell's role as honorary president, concluded that "the Guild has rendered for many years an essential service to our Catholic school children ... any curtailment or interruption of this work would be a tremendous loss," and appealed to pastors as usual for gifts of $100 to support the organization's work.

Another survey of pastors and institutions in 1959 once again indicated overwhelming dissatisfaction with the guild's services. Indeed, the guild's own statistics showed that they had only been able to fully treat parochial schools in Boston and Somerville that year. Still, they insisted that their charitable dental treatments were impactful to many students. Dr. Thomas J. Giblin, who had been directing the bus transportation program since its inception in 1920, defended the work of the guild, writing to Cardinal Cushing that "since 1920, (the guild) has transported about 400,000 parochial school children for dental treatments to the Forsyth Dental Infirmary, and to the City of Boston Health Units and all of this without a single accident or mishap to any child."

This time, however, the cardinal's good will towards the organization had run dry. The guild was usually operating in debt, especially weighed down by maintenance costs for their bus, and despite their pleas, the archbishop suspended their funding. The chancellor wrote in a letter to Dr. Giblin on July 30, 1959, that the cardinal "felt it was therefore a waste of money for the Archdiocese to pay for something, the specific character of which it could not determine," referring to discrepancies between the guild's claims and the poor results from pastoral surveys. The guild discontinued its bus services and planned a new program whereby members would examine student's teeth once a year and recommend treatments to their parents. After the major defunding of the organization in 1960, it is not clear for how much longer the guild tended to parochial students in the archdiocese, or existed as a professional organization for male Catholic dentists.