Weetamoo grew up in the Pocasset's largest and main village, Mettapoisett, on the shores of present-day Cape Cod. As Weetamoo would one day become the sachem of the Pocassets, she would endure a vision quest, a ritual normally only reserved for boys, but as Weetamoo was taking on a man's role later in her life, she would undergo this ritual also. During a vision quest, the young teenager goes into the woods and fasts for days, until their child soul is killed and they become a new person. Weetamoo underwent this ritual when she was about 14, in the year 1654. Weetamoo was as accomplished as any Pocasset boy. She was a skilled hunter, swimmer, fisherman, and was very skilled in diplomatic arts. She did have the duties of other girls in her tribe as well, such as smoking fish, cooking, and preparing animal hides for clothing.

        Weetamoo married numerous husbands in her life, many of whom were sent on their ways after being too sympathetic towards the Coatmen of Plymouth Colony and other neighboring colonies. Her first husband was Wamsutta, the oldest son of Massasoit, the sachem of all the Wampanoag tribes (which included the Pocassets). After Massasoit died in 1661, Wamsutta became the Chief of the Wampanoags. Weetamoo was proud and happy, often taking part in celebrations as the most powerful woman in all of the tribes. She did however accept many English customs. She would wear makeup and jewelry from the English often, even at strict Wampanoag rituals. The Wampanoags had always been friendly with the Coatmen, as Massasoit was the sachem who took part in the Thanksgiving Feast at Plymouth in 1621. However, when the English broke their treaty with the Wampanoags in 1621, Wamsutta went to discuss this problem with the English and died of an illness while in their care in 1622. Weetamoo believed for the rest of her life that he had been poisoned, which led to her deep hatred for the Coatmen. Weetamoo remarried, this time to Quequequanchett. It is not known what happened to this marriage but Weetamoo remarried not soon after to a native named Petonowowett. It was around this time that the King Philip's War broke out. King Philip, which was his English name but was actually known to the Wampanoags as Metacom, was married to Weetamoo's sister, Woonekanuske. Weetamoo banded together with Metacom and led an attack against the English settlers, whom they had a deep mistrust and hatred for. Weetamoo was not only a beautiful leader but also was very gifted in diplomatic skills, leading to her success with the 300 warriors or more that she led. Weetamoo also left her husband when he sided with the English and married the Narraganset Sachem, Quinapin. Quinapin gave her an English woman named Mary Rowlandson, who wrote many detailed accounts of Weetamoo and the Wampanoags in her diaries. She did not befriend Weetamoo, though she admired Quinapin. She had no idea that Weetamoo was in a sense a queen, and saw her as a ruthless and power-hungry housewife.