A belief that God is both all-powerful and personally involved in the day-to-day workings of human life is common to all branches of Christianity. For the Pilgrims, however, this belief was strengthened by a particularly strong concept of predestination; the Pilgrims, like other Calvinist-inspired sects, stressed that the future (including every individual person's salvation or damnation) was already divinely determined and that human action could not change it. While this may seem like a discouraging idea at first glance, Of Plymouth Plantation suggests that it could also be a comforting one. Because they feel so secure in their interpretation of Christianity, the Pilgrims are able to remain optimistic even in truly desperate circumstances, trusting that God will see them through. At one point, for instance, Bradford draws attention to the fact that so many Pilgrims lived into old age, having survived the early illnesses and deprivations of life in Plymouth. This, he says, is a testament to God's protection of true believers.

The corollary of this belief, at least as the Pilgrims understand it, is that any misfortune that befalls their enemies or competitors is also part of a divine plan. This at times leads Bradford to make pronouncements that sound callous to modern ears.