At the beginning of the seventeenth century, Christians are persecuted in Japan, except in the northeast region, the domain of Lord Ishida. Under orders from the shogun to create a port in the northeast to rival Nagasaki, and to open up trade routes to Europe, Lord Ishida builds a large galleon using Spanish labor and expertise. He then sends a delegation in this galleon to Mexico. On board are four envoys, including Rokumon Hasekura, the samurai of the title; the Spanish priest Father Vrais Luis Velasco, who acts as interpreter; and a group of Japanese merchants with wares to sell in the New World.

After a perilous voyage, the galleon reaches Acapulco, and the delegation proceeds overland to Mexico City. Velasco, who is overwhelmingly ambitious to become bishop of Japan and establish Christianity—and in particular the Franciscan order—on a firm footing there, contrives to have a group of Japanese merchants baptized. This secures the goodwill of the archbishop and the viceroy, who was initially reluctant to meet the Japanese delegation.

The viceroy receives his Japanese visitors, and Hasekura presents him with letters promising a warm welcome for Spanish Catholics in the northeast if a trading partnership can be established. However, the viceroy protests that he has no authority to agree to such a partnership, which requires the approval of the king in Madrid and perhaps even the pope in Rome. Velasco, who had wanted to travel on to Europe in any case, leads the delegation onward, across Mexico to Veracruz, in preparation for a voyage across the Atlantic. This is a dangerous journey, as there are insurrections against the Spanish along the route, but Velasco conceals these dangers from the Japanese envoys. One of their number, Matsuki Chusaku, who is more politically astute than the others, refuses to go with them and returns to Japan from Mexico. When the other envoys discover the danger for themselves, the most experienced soldier among them, Tanaka Tarozaemon, takes command of the expedition.

The envoys and Velasco eventually reach Veracruz and make a crossing of the Atlantic even longer and more arduous than their voyage across the Pacific to Mexico. Before they leave Veracruz, Velasco receives a letter from his uncle, who tells him that the Jesuits have been mustering opposition against his plans to send more missionaries to Japan and that he must be prepared to debate with them when he arrives in Madrid. Velasco believes that the surest way to guarantee success is to convert the Japanese envoys to Christianity.

When the envoys reach Madrid, Velasco finds that there is little enthusiasm for his project among the aristocracy or the clergy. His family try to dissuade him from proceeding. Nonetheless, Velasco goes before the Council of Bishops to debate with the Jesuit Father Valente. The debate is inconclusive, and Velasco remains certain that the bishops must be convinced by a demonstration of faith on the part of the Japanese envoys. He persuades them to undergo the rite of baptism, for the sake of the mission.

After the three envoys have been baptized, it appears that they will be accepted as ambassadors and granted an audience with the King of Spain. However, as soon as the Council of Bishops has announced this decision, news comes from Japan that Christianity has been banned there, and Christians are once again being persecuted throughout the country. Faced with an ignominious return, the envoys decide to go to Rome, to see if the pope has any better information about the situation in Japan than the Spanish king.

In Rome, the Japanese envoys and Velasco are granted an...