In Malacca in December, 1547, Francis Xavier met a Japanese man named Anjiro. Anjiro had heard of Francis in 1545 and had traveled from Kagoshima to Malacca with the purpose of meeting with him. Having been charged with murder, Anjirō had fled Japan. He told Francis extensively about his former life and the customs and culture of his beloved homeland. Anjiro helped Xavier as a mediator and translator for the mission to Japan that now seemed much more possible. Anjirō became the first Japanese Christian and adopted the name of 'Paulo de Santa Fe'.
In January 1548 Francis returned to Goa to attend to his responsibilities as superior of the mission there. The next 15 months were occupied with various journeys and administrative measures. He left Goa on 15 April 1549, stopped at Malacca and visited Canton. He was accompanied by Anjiro, two other Japanese men, the father Cosme de Torrès and Brother João Fernandes. He had taken with him presents for the "King of Japan" since he was intending to introduce himself as the Apostolic Nuncio.
Europeans had already come to Japan: the Portuguese had landed in 1543 on the island of Tanegashima, where they introduced the first firearms to Japan.
From Amboina, he wrote to his companions in Europe: "I asked a Portuguese merchant, … who had been for many days in Anjirô’s country of Japan, to give me … some information on that land and its people from what he had seen and heard …. All the Portuguese merchants coming from Japan tell me that if I go there I shall do great service for God our Lord, more than with the pagans of India, for they are a very reasonable people. (To His Companions Residing in Rome, From Cochin, January 20, 1548, no. 18, p. 178).
Francis Xavier reached Japan on 27 July 1549, with Anjiro and three other Jesuits, but he was not permitted to enter any port his ship arrived at until 15 August, when he went ashore at Kagoshima, the principal port of the province of Satsuma on the island of Kyushu. As a representative of the Portuguese king, he was received in a friendly manner. Shimazu Takahisa (1514–1571), daimyo of Satsuma, gave a friendly reception to Francis on 29 September 1549, but in the following year he forbade the conversion of his subjects to Christianity under penalty of death; Christians in Kagoshima could not be given any catechism in the following years. The Portuguese missionary Pedro de Alcáçova would later write in 1554:
In Cangoxima, the first place Father Master Francisco stopped at, there were a good number of Christians, although there was no one there to teach them; the shortage of laborers prevented the whole kingdom from becoming Christian.
He was hosted by Anjiro's family until October 1550. From October to December 1550, he resided in Yamaguchi. Shortly before Christmas, he left for Kyoto but failed to meet with the Emperor. He returned to Yamaguchi in March, 1551, where he was permitted to preach by the daimyo of the province. However, lacking fluency in the Japanese language, he had to limit himself to reading aloud the translation of a catechism.
Francis was the first Jesuit to go to Japan as a missionary. He brought with him paintings of the Madonna and the Madonna and Child. These paintings were used to help teach the Japanese about Christianity. There was a huge language barrier as Japanese was unlike other languages the missionaries had previously encountered. For a long time Francis struggled to learn the language.
Having learned that evangelical poverty had not the appeal in Japan that it had in Europe and in India, he decided to change his method of approach. Hearing after a time that a Portuguese ship had arrived at a port in the province of Bungo in Kyushu and that the prince there would like to see him, Xavier now set out southward. The Jesuit, in a fine cassock, surplice, and stole, was attended by thirty gentlemen and as many servants, all in their best clothes. Five of them bore on cushions valuable articles, including a portrait of Our Lady and a pair of velvet slippers, these not gifts for the prince, but solemn offerings to Xavier, to impress the onlookers with his eminence. Handsomely dressed, with his companions acting as attendants, he presented himself before Oshindono, the ruler of Nagate, and as a representative of the great kingdom of Portugal offered him the letters and presents, a musical instrument, a watch, and other attractive objects which had been given him by the authorities in India for the emperor.
For forty-five years the Jesuits were the only missionaries in Asia, but the Franciscans also began proselytizing in Asia as well. Christian missionaries were later forced into exile, along with their assistants. Some were able to stay behind, however Christianity was then kept underground as to not be persecuted.
The Japanese people were not easily converted; many of the people were already Buddhist or Shinto. Francis tried to combat the disposition of some of the Japanese that a God who had created everything, including evil, could not be good. The concept of Hell was also a struggle; the Japanese were bothered by the idea of their ancestors living in Hell. Despite Francis' different religion, he felt that they were good people, much like Europeans, and could be converted.
Xavier was welcomed by the Shingon monks since he used the word Dainichi for the Christian God; attempting to adapt the concept to local traditions. As Xavier learned more about the religious nuances of the word, he changed to Deusu from the Latin and Portuguese Deus. The monks later realized that Xavier was preaching a rival religion and grew more aggressive towards his attempts at conversion.
With the passage of time, his sojourn in Japan could be considered somewhat fruitful as attested by congregations established in Hirado, Yamaguchi and Bungo. Xavier worked for more than two years in Japan and saw his successor-Jesuits established. He then decided to return to India. Historians debate the exact path he returned by, but from evidence attributed to the captain of his ship, he may have traveled through Tanegeshima and Minato, and avoided Kagoshima because of the hostility of the Daimyo. During his trip, a tempest forced him to stop on an island near Guangzhou, China where he saw the rich merchant Diogo Pereira, an old friend from Cochin, who showed him a letter from Portuguese being held prisoners in Guangzhou asking for a Portuguese ambassador to talk to the Chinese Emperor in their favor. Later during the voyage, he stopped at Malacca on 27 December 1551, and was back in Goa by January, 1552.
On 17 April he set sail with Diogo Pereira, leaving Goa on board the Santa Cruz for China. He introduced himself as Apostolic Nuncio and Pereira as ambassador of the King of Portugal. Shortly thereafter, he realized that he had forgotten his testimonial letters as an Apostolic Nuncio. Back in Malacca, he was confronted by the capitão Álvaro de Ataíde da Gama who now had total control over the harbor. The capitão refused to recognize his title of Nuncio, asked Pereira to resign from his title of ambassador, named a new crew for the ship and demanded the gifts for the Chinese Emperor be left in Malacca.
In late August, 1552, the Santa Cruz reached the Chinese island of Shangchuan, 14 km away from the southern coast of mainland China, near Taishan, Guangdong, 200 km south-west of what later became Hong Kong. At this time, he was only accompanied by a Jesuit student, Álvaro Ferreira, a Chinese man called António and a Malabar servant called Christopher. Around mid-November he sent a letter saying that a man had agreed to take him to the mainland in exchange for a large sum of money. Having sent back Álvaro Ferreira, he remained alone with António. He died at Shangchuan from a fever on 3 December 1552, while he was waiting for a boat that would agree to take him to mainland China.