In 2017, Chau participated in 'boot camp' missionary training by the Kansas City-based evangelical organization All Nations. According to a report by The New York Times, the training included navigating a mock native village populated by missionary staff members who pretended to be hostile natives, wielding fake spears.During that year, he reportedly expressed his interest in converting the Sentinelese.

In October 2018, Chau traveled to and established his residence at Port Blair, capital of the Andaman and Nicobar Islands, where he prepared an initial contact kit including picture cards for communication, gifts for Sentinelese people, medical equipment, and other necessities. In August 2018, the Indian Home Ministry had removed 29 inhabited islands in Andaman and Nicobar from the Restricted Area Permit (RAP) regime, in an attempt to promote tourism. However, visiting North Sentinel Island without government permission remained illegal under the Andaman and Nicobar Islands (Protection of Aboriginal Tribes) Regulation, 1956.

In November, Chau embarked on a journey to North Sentinel Island, which he thought could be "Satan's last stronghold on Earth",with the aim of contacting and living among the Sentinelese. In preparation for the trip, he was vaccinated and quarantined, and also undertook medical and linguistic training.

Chau paid two fishermen ₹25,000 (equivalent to ₹33,000 or US$400 in 2023) to take him near the island. The fishermen were later arrested.

Chau expressed a clear desire to convert the tribe and was aware of the legal and mortal risks he was taking by his efforts, writing in his diary, "Lord, is this island Satan's last stronghold, where none have heard or even had the chance to hear your name?", "The eternal lives of this tribe is at hand", and "I think it's worthwhile to declare Jesus to these people. Please do not be angry at them or at God if I get killed ... Don't retrieve my body."

On November 15, Chau attempted his first visit in a fishing boat, which took him about 500–700 meters (1,600–2,300 ft) from shore. The fishermen warned Chau not to go farther, but he canoed toward shore with a waterproof Bible. As he approached, he attempted to communicate with the islanders and to offer gifts, but he retreated after facing hostile responses.

On another visit, Chau recorded that the islanders reacted to him with a mixture of amusement, bewilderment, and hostility. He attempted to sing worship songs to them, and spoke to them in Xhosa, after which they often fell silent. Other attempts to communicate such as echoing the tribesmen's words ended with them bursting into laughter, making Chau theorize that they were cursing at him.Chau stated they communicated with "lots of high-pitched sounds" and gestures. Eventually, according to Chau's last letter, when he tried to hand over fish and gifts, a boy shot a metal-headed arrow that pierced the Bible he was holding in front of his chest, after which he retreated again.

On his final visit, on November 17, Chau instructed the fishermen to abandon him. The fishermen later saw the islanders dragging Chau's body, and the next day they saw his body being buried on the shore.