Little is known about the life of Cockacoeske before she succeeded her husband, Totopotomoy, chief of the Pamunkey from about 1649 until he was killed in 1656 while assisting the colonists in frontier defense against Indian foes. She was usually referred to as the queen of Pamunkey. By the time Cockacoeske commenced her rule, the ancient Powhatan chiefdom had disintegrated, and the Indians of Virginia's coastal plain were no longer subordinate to a paramount leader. The Pamunkey, like other native subscribers to the Treaty of 1646, were tributaries to the English Crown.

Early in the summer of 1676 Cockacoeske appeared before a committee of burgesses and Council members in Jamestown. She entered the room with regal bearing, flanked by her interpreter and by her son John West, whose father was an English colonel. The queen's head was crowned with a broad woven band of beaded black and white wampum and peake shells, and she wore a full-length deerskin mantle with edges cut to resemble deep, twisted fringe. With "grave Courtlike Gestures and a Majestick Air," she took a seat at the Council table and refused to speak except through her interpreter, even though the committee members believed that she understood English. When asked how many warriors she could provide to defend the colony against frontier tribes, Cockacoeske disdainfully fell silent. Pressed further, she became agitated and delivered a quarter-hour speech during which she cried out, "Tatapatamoi Chepiack," meaning, "Totopotomoy is dead," to remind the committee members that her husband and a hundred of his warriors had perished while fighting alongside the colonists and that the Pamunkey had never received any compensation for their loss. Reluctantly, she eventually agreed to provide a dozen men, a small fraction of the number under her command. Conflict and disease had reduced the Native American population since 1607, but the number of Pamunkey warriors was then probably about 150.

Although the Pamunkey signed a treaty with the colony in March 1676, a few months before the outbreak of Bacon's Rebellion, the insurrection's leader, Nathaniel Bacon (1647–1676), and his followers attacked them, took captives and plunder, and killed some of Cockacoeske's people. To save her own life, the queen abandoned her goods and possessions, including bags of wampum, peake, and roanoke, and retreated to the depths of the Dragon Swamp, where she nearly starved to death. The following February, Cockacoeske asked the General Assembly for the release of Pamunkey who had been taken captive and for the restoration of Pamunkey property. The burgesses were unresponsive, but the royal commissioners whom the king had sent to quell the rebellion and investigate its origins concluded that Cockacoeske should be rewarded for her notable loyalty to the English. At their suggestion, authorities in England ordered that a jeweled coronet, other jewelry, and a suit of regal attire be presented to the queen of Pamunkey, her son, and her interpreter.

Cockacoeske was an astute leader and skillful politician. On May 29, 1677, when the Treaty of Middle Plantation was signed, at her request several tribes were reunited under her authority, and she signed the treaty on behalf of all the tribes under her subjection. Afterward, the Chickahominy and Rappahannock, having been free of Powhatan domination since 1646, stubbornly refused to become subservient to her or to pay tribute, and in the summer of 1678 Cockacoeske directed her interpreter Cornelius Dabney to compile a list of grievances, which she sent to the governor. She also had him dispatch to England a letter in which she professed her loyalty to the Crown and complained about the tribes that disobeyed her orders. The letter, signed "Cockacoeske Queen of Pamunkey," included her signature mark, the same W-like symbol that she had affixed to the Treaty of Middle Plantation.

Cockacoeske was unsuccessful in re-creating the chiefly dominance enjoyed by her people's leaders during the first half of the seventeenth century, but she continued to rule the Pamunkey until her death. Cockacoeske, the queen of Pamunkey, died on an unrecorded date before July 1, 1686, when her interpreter George Smith reported to the governor's Council that she was "lately dead." She was succeeded by a niece, as was customary in the matrilineal society. Whether the niece, called Betty, was the predecessor of or the same person as Ann, who was queen of the Pamunkey by 1706, is not known.