Founded in 1622 by Pope Gregory XV's bull Inscrutabili Divinae, the body was charged with fostering the spread of Catholicism and with the regulation of Catholic ecclesiastical affairs in non-Catholic countries. The intrinsic importance of its duties and the extraordinary extent of its authority and of the territory under its jurisdiction caused the Cardinal Prefect of Propaganda to be known as the "red pope".
At the time of its inception, the expansion of colonial administrations was coming to be largely in Dutch and English hands, both Protestant countries intent on spreading these religious doctrines, and Rome perceived the very real threat of Protestantism spreading in the wake of commercial empire. By 1648, with the end of the Thirty Years' War, the official religious balance of established Christianity in Europe was permanently stabilized, but new fields for evangelization were offered by vast regions of Asia, Africa, and the Americas then being explored.
There had already been a less formally instituted cardinal committee concerned with propaganda fide since the time of Pope Gregory XIII (1572–1585), which were especially charged with promoting the union with Rome of the long-established eastern Christian communities: Slavs, Greeks, Syrians, Egyptians, and Abyssinians. This was the traditional direction for the Catholic Church to look for evangelizing. Catechisms were printed in many languages and seminarians sent to places as far as Malabar. The most concrete result was the union with Rome of the Ruthenian Catholic communion, most concentrated in modern-day Ukraine and Belarus; the union was formalized at Brest in 1596.
The death of Gregory XV the following year did not interrupt the organization, because Cardinal Barberini, one of the original thirteen members of the congregation, became the next pope as Urban VIII (1623–1644). Under Urban VIII, a central seminary (the Collegium Urbanum) was set up for training missionaries. The Congregation also operated the polyglot printing press in Rome, printing catechisms in many languages. Their procurators were especially active in China from 1705, moving between Macau and Canton before finally settling in Hong Kong in 1842.
In strongly Protestant areas, the operations of the Congregation were considered subversive: the first missionary to be killed was in Grisons, Switzerland, in April 1622, before the papal bull authorizing its creation had been disseminated. In Ireland after Catholic emancipation (1829) while the established church was still the Protestant Church of Ireland, the Irish Catholic church came under the control of the Congregation in 1833, and soon reformed itself with a devotional revolution under Cardinal Cullen.
The Holy See removed the United States from the jurisdiction of Propaganda Fide as mission territory in 1908, along with England, the Netherlands, Luxemburg, and Canada.
These "Cardinals in General Congregation" met weekly, keeping their records in Latin until 1657, then in Italian. The minutes are available in microfilm (filling 84 reels) at large libraries. In the course of their work, the Propaganda fide missionaries accumulated the objects now in the Vatican Museum's Ethnological Missionary Museum.
Since 1989 the incumbent Prefect is also President of the Interdicasterial Commission for Consecrated Religious.
In 2014 Sr. Luzia Premoli, superior general of the Combonian Missionary Sisters, was appointed a member of the Congregation for the Evangelization of Peoples, thus becoming the first woman to be appointed a member of a Roman curial congregation.