Tisquantum was a native of Patuxet, living at present-day Plymouth; the Patuxet belonged to the Wampanoag confederation. Nothing is really known about Squanto's early life. His history picks up in 1614, when Captain John Smith and some of other ships under his command arrived to map Cape Cod and vicinity. John Smith is perhaps better known for having been rescued by Pocahontas at the Jamestown Colony several years earlier. After Smith completed his exploration and mapping of the harbors, he departed, leaving behind an associate, Thomas Hunt, to trade with the Indians. John Smith had hopes of founding a plantation in New England, and so wanted to engage the Indians in trade.

Thomas Hunt, however, had other plans. Offering to trade beaver, Hunt lured 24 Nauset and Patuxet Indians onboard his ship and took them captive. John Smith would later write that Master Hunt "most dishonestly, and inhumanely, for their kind usage of me and all our men, carried them with him to Malaga, and there for a little private gain sold those silly salvages for rials of eight." Sir Ferdinando Gorges, head of the Council for New England, remembered it similarly: "one Hunt (a worthless fellow of our nation) set out by certain merchants for love of gain; who (not content with the commodity he had by the fish, and peaceable trade he found among the savages) after he had made his dispatch, and was ready to set sail, (more savage-like than they) seized upon the poor innocent creatures, that in confidence of his honesty had put themselves into his hands."

Hunt stored the Indians below the hatches, and sailed them to the Straits of Gibraltar, and on to the city of Malaga, Spain, where he sold as many of them as he could. But when some local Friars in Malaga discovered that they had been brought from America, they took custody of the remaining Indians, and instructed them in the Christian faith. As Sir Ferdinando Gorges states, the Friars "so disappointed this unworthy fellow of the hopes of gain he conceived to make by this new and devilish project."

The Nauset and Patuxet tribes were outraged by the kidnappings, and became extremely hostile. English and French ships visiting Plymouth and Cape Cod were no longer welcomed with profitable beaver trade, as an unwitting French captain and crew would discover in 1617, when their ship was burned and almost everyone killed (a few were enslaved) by the Nauset.

But outrage and vengeance against Europeans would soon become a low priority amongst the Nauset and Patuxet. In 1618 and 1619, a devastating plague, described variously in historical sources as either tuberculosis or smallpox (and perhaps a combination of both), wiped out the entire village at Patuxet, and many surrounding areas were heavily hit.

One Patuxet did survive, however: Tisquantum. He had somehow found himself passage from Malaga, Spain into England, where he began living with John Slaney in Cornhill, London, and began picking up the English language. John Slaney was the treasurer of the Newfoundland Company which had managed to place a colony at Cupper's Cove (Cupids), Newfoundland in 1610; he employed Tisquantum, presumably as an interpreter and as an expert on North American natural resources. He was sent to Newfoundland, and worked there with Captain John Mason, governor of the Newfoundland Colony.

While in Newfoundland, Tisquantum encountered a ship's captain by the name of Thomas Dermer, who had worked with Captain John Smith, perhaps even on the 1614 mapping expedition in which Squanto had been originally taken. Dermer was employed by the New England Company, headed by Sir Ferdinando Gorges; they still had hopes to profit from beaver trade with the Indians of Massachusetts: but this would not be possible as long as hostilities remained. Thomas Dermer recognized that Tisquantum, who had now been living with Englishmen for a number of years, could act as an interpreter and peacemaker between the English and the still-enraged Indians of Patuxet and Nauset. He sent a letter off to Sir Ferdinando Gorges expressing the good use Tisquantum could be put to, and Gorges had them come back to England to discuss their plans.

In 1619, Captain Dermer and Tisquantum set off for New England, to attempt to make peace and re-establish trade with the Indians, and to map out the natural resources that could be exploited by the Company. But upon arriving, they discovered Tisquantum's town, all the Patuxet, were dead from the plague. He did make contact with Massasoit, and his brother Quadequina, the heads of the Wampanoag Confederation, and in the absence of his own people he took up residence with them. Their plan to make peace foiled by the fact that Tisquantum's tribe had been completely wiped out, Dermer continued on to see if he could make peace with the Nauset. He was attacked and taken captive. Tisquantum, hearing about the incident, came to Dermer's rescue and negotiated his release. Dermer would continue on south without Tisquantum, where he was attacked again at Martha's Vineyards. He would die of the wounds after reaching Jamestown, Virginia.

Tisquantum's return home in 1619 was just in time for the Mayflower Pilgrims, who pulled into Provincetown Harbor in November 1620. The Pilgrims sent out their own exploration parties, and during their third expedition they were attacked in camp early one morning by the Nauset. Shots were fired and arrows flew heavily, but in the end nobody was injured and the Nauset fled back into the woods. The Pilgrims continued their expedition around Cape Cod, eventually ending up in the abandoned Patuxet territory, where they decided to settle (the area had been named Plymouth by John Smith on his 1614 mapping expedition).