Mersenne is perhaps best known as Descartes’ principal correspondent during the latter's residence in the Netherlands from 1629 until Mersenne's death. He assisted in the publication of Descartes’ Discourse on Method in 1637 and gathered the Objections to the Meditationes (1641). Mersenne also corresponded prodigiously with many other philosophers throughout Europe, acting as intelligencer and clearinghouse, communicating ideas and mediating disputes.

Mersenne was educated by the Jesuits, entering the newly founded Jesuit College of La Flèche in 1604, where he was an older contemporary of Descartes. Mersenne left La Flèche in about 1609 to study theology in Paris, at both the Sorbonne and the Collège de France. In 1611 he entered the Order of Minims, joining its Parisian convent off the Place Royale (now Place des Vosges) in 1619 and living there for the rest of his life.

Mersenne numbered Protestants as well as Catholics among his correspondents and strove to overcome their doctrinal divisions. Unlike his early, published assaults on heresy, this generally took the form of promoting a moderate, reconciliatory form of Catholicism. He never changed his perception of the dangers of skepticism, however, and his so-called mitigated skepticism amounted to a philosophical irenicism to match the religious.

Mersenne's engagement with the work of his philosophical contemporaries extended well beyond Descartes’ writings. During the 1630s, Mersenne promoted the work of Galileo; met and corresponded with Isaac Beeckman; and brought back to France from Italy in 1645 knowledge of the Torricellian barometric experiment, which led to Blaise Pascal's celebrated work on the weight of the air.

Mersenne early confronted Pyrrhonian skepticism. By the mid-1620s he had come to see it as just one example of a whole range of philosophical positions that threatened religious and social stability. The most common tactic of its opponents in France at this time was to counter Pyrrhonian arguments piecemeal, but Mersenne attacked Pyrrhonism by developing an epistemology to act as a bulwark against skepticism. Mersenne's interest in natural philosophy and in the mathematical sciences contributed to this approach.