Coosaponakeesa was born in 1700 in Coweta, in the Lower Creek Nation, near what is now Macon, Georgia. Her mother belonged to the Wind Clan and was the sister of the chief mico of the Lower Creek (known as Old Brim to the English). Her father may have been an English trader. When she was ten years old she was sent to Charles Town, South Carolina and stayed with an English family. There she went to school, learned to speak English, was baptized, and given the English name of Mary.

Coosaponakeesa returned to Coweta in 1715. This was a time of great unrest in the area. Many Indian tribes were upset over abusive trading practices, and the Yamasee went to war against the British Carolina settlements in 1714. In 1716 peace was restored, but the British wanted to make sure the Creeks remained their allies, and held talks with the tribe to work out satisfactory agreements. During one of these talks Colonel John  Musgrove visited Coweta to establish a border treaty between the Creeks and the Carolina settlements. His son John accompanied him on this visit. John and Coosaponakeesa were married as part of the treaty negotiations. They lived with the Creeks until 1725, then moved back to Charles Town.

Several years later the Creeks invited the British to build a trading post in Creek territory, and requested that it be run by an Indian. The British chose Coosaponakeesa and her husband John Musgrove. In 1730 they moved to Yamacraw, a village founded by Coosaponakeesa's relative Tomo-chi-chi in 1725. Tomo-chi-chi had provided land north of Yamacraw on the Altamaha River for the trading post. He also gave Coosaponakeesa 500 acres of land on which to build her house, making it clear that the land was hers (British law at the time prohibited women from owning property). This 500 acres eventually grew into the city of Savannah, Georgia.

Coosaponakeesa spoke Muskogean (Creek), English, and the Mobilian trade language. She acted as interpreter for Tomo-chi-chi in any talks with the English. In early 1733 James Oglethorpe arrived at Yamacraw and began discussions with the Creeks that led to the establishment of a colony there, to be settled by debtors from England. Coosaponakeesa acted as interpreter in these discussions, which led to the establishment of the British colony of Georgia. During the colony's early years, her plantation was one of it's main food suppliers.

In 1734 Oglethorpe planned a trip to England and invited Tomo-chi-chi and a delegation of Creeks to go along. Coosaponakeesa was to go as interpreter, but her parents fell ill before the ship sailed, and John Musgrove went in her place.

After his return from England in 1735 Tomo-chi-chi ordered the construction of a school near Savannah where Creek children would be taught to read and write English. Coosaponakeesa, who had taught Tomo-chi-chi's nephew Toonahowie to read and write, helped teach in the school. But her husband John died later that year, and she had to run their trading post, Mount Venture.

Coosaponakeesa married her second husband, Jacob Matthews, in 1737. She became wealthy and influential among the Creeks and Georgians. When the Georgia colony produced it's first silk in 1739, it was sent to England to be woven into cloth. One bolt was sent to the British queen, another was sent to Coosaponakeesa. Britain and Spain went to war in the same year, and the Creeks sided with the British, due in large part to Coosaponakeesa's influence. She supplied the British with money, gunpowder, and weapons. The British won the war.

The Creeks had given Coosaponakeesa thousands of acres of land along the Savannah River and, Sapelo, Ossabaw, and St. Catherine's islands off the Georgia coast. But Britain refused to recognize her land holdings. Coosaponakeesa was Creek, but her husband was a British subject. Under British law individuals could not accept land grants from Indians, and women couldn't own property.

The Creeks considered the British position towards Coosaponakeesa's lands as an insult to Creek sovereignty. The land was reserved for the Creeks in the treatys that allowed the formation of the Georgia colony, and since Coosaponakeesa was Creek they had every right to grant it to her. Jacob Matthews died in 1745 and Coosaponakeesa married Thomas Bosomworth in 1747. When Bosomworth assisted her in pressing her claims to the land, he was accused of treason by Georgia, aggravating the situation even more.

In 1749 Coosaponakeesa and Bosomworth led a group of Creeks, including Malatchi, then chief mico of the tribe, in a protest march on Savannah. Coosaponakeesa and Bosomworth were arrested, but they were later released after apologizing to Savannah officials. They then traveled to England and presented her claim to the British Board of Trade. Eventually a compromise was reached in 1759 in which Sapelo and Ossabaw islands would be auctioned off, with the proceeds going to Coosaponakeesa, and she would get title to St. Catherine's Island from the British Crown "in consideration of services rendered by her to the province of Georgia".

 Coosaponakeesa had spent more than 20 years trying to get the British government, to which she had provided so much invaluable aid, to recognize her claim to land that had been given to her by her people, the Creek Nation, which had also been an ally of critical importance to the British. She settled on St. Catherine's in 1760. When Coosaponakeesa died 5 years later, St. Catherine's Island was inherited by her British husband, in accordance with British law.