Picking up after the events of "The Young Pope", Pope Pius XIII is in a coma after suffering a heart attack, leaving the Holy See searching for his replacement.

In the midst of conflicting interests rises Sir John Brannox, a British intellectual known for a theological text he wrote in his earlier days. Religiously moderate and sophisticated, he hides secrets that weigh heavily upon him.

As he is elected to the papal throne, Brannox assumes the name of John Paul III, but realizes that his predecessor's devoted cult is hard to win over as they anticipate his return.