Yasuke arrived in Japan in 1579 as the servant of the Italian Jesuit Alessandro Valignano, who had been appointed the Visitor (inspector) of the Jesuit missions in the Indies, i.e. S. and E. Asia, an extremely high position, so he must have been quite trust-worthy. He accompanied Valignano when the latter came to the capital area in March of 1581 and caused something of a sensation. Nobunaga heard about him and expressed a desire to see him. He thought the black color might be paint, so he had him strip from the waist up. Nobunaga's nephew gave him money. In May, Yasuke accompanied a group of Jesuits on a short trip to the province of Echizen. Yasuke could speak some Japanese, so Nobunaga enjoyed talking with him and was also impressed by his strength. At Nobunaga's request, Valignano left Yasuke with Nobunaga before Valignano left central Japan later that year. Nobunaga treated Yasuke with great favor. "People even say he will be made a 'tono' (lord)," though this did not happen.

In June 1582, Nobunaga was attacked and killed in Honnō-ji in Kyoto by the army of Akechi Mitsuhide. Yasuke was there at the time. Immediately after Nobunaga's death, Yasuke went to the lodging of Nobunaga's heir Oda Nobutada, apparently withdrew with him to Nijô Castle, and when that too was attacked by Akechi, fought for a long time. Finally he surrendered his sword to Akechi's men. They asked Akechi himself what to do with him. Akechi said that the black man was a beast and did not know anything, and furthermore, he was not Japanese, so they should not kill him but take him to the church [in Kyoto] of the Visitor from India, so they did, much to the relief of the Jesuits there who had worried about him. There is no information about him after that.

The "Lord Nobunaga Chronicle" (信長公記 Shinchōkōki) has a description of Yasuke's first meeting with Nobunaga. "On the 23rd of the 2nd month [March 23, 1581], a black page (黒坊主 "kuro-bōzu") came from the Christian countries. He looked about 26 [24 or 25 by Western count] or 27 years old; his entire body was black like that of an ox. The man was healthy and good-looking. Moreover, his strength was greater than that of 10 men."