While preaching in Casco, Maine (now Portland) in 1676, the entire settlement was broken up by an Indian assault. Burroughs escaped to an island in the Bay. He was rescued by aid from the mainland. He moved to the Village of Salem in 1680, where a year later his wife died. Burroughs ministered in the Village of Salem for only two years. He left as a result of a bitter dispute over his salary. He seems also to have had a more personal and heated dispute over money with John Putnam, the uncle of one of Burroughs' later accusers. As a result of these disputes, Burroughs left the Village abruptly. After leaving Salem, he returned to Casco, where he was again driven out by Indians in 1683, causing him to relocate to Wells, Maine. There he was given a grant of 150 acres of land, part of which he gave back to the city as population thickened.

Burroughs had been serving as a minister in Wells for nine years when he was arrested for witchcraft. He was seized, taken from the table while eating, and hauled back to Salem on May 4 to stand trial. The arrest and examination of Burroughs "constituted the most dramatic escalation of judicial action during the early phases of the trials." Burroughs was tried on August 5. There was no shortage of testimony that Burroughs was not just a witch, but their leader as well. One of his accusers testified that his specter told her that "he was above a witch, he was a conjurer." During his examination “trial”, the suffering of the afflicted girls was so extreme that the magistrates ordered them removed from the court house for their own safety. Abigail Hobbs confessed that magical dolls had been given to her by Burroughs. Nineteen-year-old Mercy Lewis claimed that Burroughs "carried me up to an exceeding high mountain and shewed me all the kingdoms of the earth and tould me that he would give them all to me if I would writ in his book," a temptation not unlike one used by his supposed master on occasion. Some of the most damaging testimony against Burroughs was by several confessed witches who identified him as Satan's personal representative at Salem Sabbaths. They claimed that meetings were personally organized and presided over by Sorcerer Burroughs. The effect of this testimony was to convince the magistrates that they had finally located one of the central figures in the current diabolical operations. Much of the testimony, however, in addition to focusing on his commissions of acts of witchcraft, focused on his general mistreatment of his wives, and his uncanny physical ability. Ann Putnam claimed to have been visited by two women in shrouds (the deceased wives of Burroughs) who proclaimed to her the mistreatment they suffered at the hands of their husband. Burroughs was a short man of small build, who supposedly possessed superhuman strength. Burroughs was accused on one occasion of having carried a whole barrel of molasses or cider a great distance. He responded that at the time an Indian had done the same, and his accusers immediately replied that his Indian companion had to have been the Devil. It was also said that Burroughs could run faster than a horse, and would often go from one location to the next in a shorter time than was possible for a mere mortal. Burroughs again responded that he had a companion on these travels, and it was again alleged that this companion was the Devil.

Despite the wealth of testimony against him, historical records have credited Burroughs with many character traits uncommon for a wizard (male witch). There is "evidence that he was self-denying, generous, and public spirited, laboring with humility and with zeal." By another account "he was an able, intelligent, true-minded man; ingenuous, sincere, humble in his spirit, faithful and devoted as a minister, and active, generous and disinterested as a citizen." These are hardly the characteristics one would expect to find in a close companion of Satan. Papers in the State house in Maine indicate that he was regarded with confidence by his neighbors and looked up to as a friend and counselor. As a result of his untarnished record, despite the danger to themselves, thirty-two of the most respectable citizens of the Village signed a petition on behalf on Burroughs' innocence, and even before his execution, one of his accusers recanted her accusation as groundless and made out of fear. It was no use. Burroughs was hanged on August 17 along with three other men and one woman, all supposed witches.

As he stood on the gallows awaiting the noose, Buroughs stunned the crowd by loudly proclaiming his innocence and then reciting the Lord's Prayer without hesitation or error, a feat thought impossible for a wizard. The spectators, deeply impressed, called for his pardon. However, more legal-minded officials overseeing the execution refused, and the convicted man was hanged before the protesting spectators could organize their opposition. A somewhat disputed account claims that after the hanging his body was cut down, dragged by the halter, thus becoming partially disrobed, thrown in a hole between the rocks, and left, partially buried with two others who had been hanged. It is interesting to note that many of the depositions against Burroughs were obtained after his trial and execution in order to help bolster the verdict. About twenty years later his children were given monetary compensation from the government for their father's wrongful execution.