Kemys was unintentionally instrumental in the sequence of events that led to the final downfall and execution of Raleigh after leading a party of Raleigh's men in an attack on the Spanish outpost of Santo Tomé on the Orinoco River, against Raleigh's orders, and in violation of peace treaties with Spain. Raleigh's son Wat was killed during the attack. A condition of Raleigh's release from the Tower of London in 1616 to undertake his mission to Guiana in search of gold deposits had been that he not attack or harass Spanish colonies or shipping. As Raleigh had been under a suspended death sentence for treason since 1603, the fact that men under his command had violated this order meant that James I would have had little option but to enforce this earlier sentence.
Kemys had sailed with Raleigh to Guiana in search of gold with which Raleigh hoped to buy back a degree of royal favour. Because of his history of antagonism with the Spanish, it was required that Kemys, and not Raleigh lead the expedition onto the mainland. The sequence of events that led to Kemys' attack on Santo Tomé in January 1618 is unclear, with English and Spanish sources offering differing accounts of the incident, and each accusing the other of having fired the first shots, but it seems unlikely that Kemys intended the eventual result that transpired. Raleigh's son Wat was the first casualty of the brief skirmish, killed by a musket ball. One other Englishman and two Spaniards were also killed, before the Spanish garrison fled. Kemys' men found themselves in control of the town, but surrounded by hostile Spanish forces. Kemys sent out a few brief expeditions in search of the promised gold, but these were unsuccessful. After 29 days and failed attempts to negotiate with the Spanish, Kemys ordered Santo Tomé looted and burned. They set off back down the Orinoco to rejoin Raleigh and their fleet, finally arriving back there on 2 March.
Kemys had already informed Raleigh by letter of the unfolding disaster and the death of his son. He went to Raleigh's cabin to beg forgiveness, but found Raleigh unable to grant him this. In Raleigh's words "I told him that he had undone me by his obstinacy, and that I would not favour... in any sort his former follie." Kemys reportedly replied "I know then, Sir, what course to take." before returning to his own cabin. Keyms then committed suicide by shooting himself in the chest with a pistol, then when that did not prove immediately fatal, stabbing himself in the heart with a knife.