Blaxton was born in County Durham, England, and attended Cambridge University, earning a bachelor's degree in 1617 and a master's in 1621. He then became an Anglican priest, although he had several disagreements with the church. This led to his decision to join the failed Gorges expedition to America in 1623.
He arrived in Weymouth, Massachusetts, in 1623 as a chaplain in the Robert Gorges expedition. Following the departure back to England of most of his fellow travellers, in 1625, he became the first European to settle in Boston, living alone on what would become Boston Common and Beacon Hill.
The Puritans landed in nearby Charlestown in 1629, and in 1630 Blackstone invited them to settle on his land in Boston after they had problems finding potable water. The Puritans then granted Blackstone 50 acres (200,000 m2) of his own land, which he promptly sold back to them.
"According to Louise Lind, author of William Blackstone: Sage of the Wilderness (1993), the cause of the conflict with the Puritans was that Blackstone was an ordained minister of the Anglican Church. The Puritans accused him of trying to bring the established Church of England to the new country. The Puritan court ordered his house burned down."[unreliable source?]
"While the Puritans also disagreed with leaders of the established Church, they proved to be quite intolerant of anyone who disagreed with them. Blackstone soon tired of their intolerance, and moved about 35 miles (56 km) south of Boston, to a hill overlooking a wide bend in what the Indians then called the Patucket (sic) River and what is today known as the Blackstone River." 
Blackstone was the first European settler in Rhode Island in 1635, before Roger Williams founded his colony the next year in Providence. The area Blackstone settled in was part of the Plymouth, then Massachusetts colony until 1741, when it became part of Rhode Island.
Blackstone's home and farm was located in what is now Cumberland, Rhode Island, on the river which bears his name. Blackstone called his home "Study Hill"—he was said to have the largest library in the colonies at the time. (His library and house were burned during King Philip's War circa 1675.) He tended cattle, planted gardens, and cultivated an apple orchard. He cultivated the first variety of American apples, the Yellow Sweeting. The farm was in the Lonsdale area of Cumberland. The site is now occupied by the Ann & Hope mill.
Although Roger Williams and Blackstone disagreed on many theological matters, "both agreed on the right to disagree, and Williams invited Blackstone to regularly preach to his followers in Providence. Blackstone continued preaching in various parts of Rhode Island and is considered to be the pioneer clergyman of the Protestant Episcopal Church in the United States."
"He preached his brand of tolerant Christianity to American Indians under an oak tree that became an inspiration to Christians worldwide." When he preached in Cumberland, he did it under a large oak tree near his home. The tree survived for centuries until the Hurricane of 1938 toppled it.
Blackstone (Blaxton) briefly returned to Boston in 1659 riding on a bull, and, at the age of 64, married Sarah Fisher Stevenson, a widow. William and Sarah had only one child, John. Sarah died at the age of 48, and Blackstone died in 1675 at the age of 80, leaving substantial holdings in real estate.
- Blackstone, Massachusetts
- Blackstone River
- Blackstone River Valley National Heritage Corridor
- Blackstone Canal
- Blackstone Street in Boston
- Blackstone Boulevard, Providence
- William Blackstone Memorial Park in Cumberland, Rhode Island 
- Plaque on Beacon Street in Boston marking the site of his house 
- Plaque on Boston Common commemorating the sale of his land 
- Timothy Blackstone, industrialist
- Thomas Coffin Amory. William Blackstone, Boston's first inhabitant, 2nd ed. Boston: Rockwell & Churchill, 1877. Google books
- B.F. DeCosta. William Blackstone in his relation to Massachusetts and Rhode Island. NY: Mallory, 1880. Google books
- "New England in the Earliest Days", A. L. Rowse, American Heritage, May 22, 1959
- The story of William Blackstone, with local color, from the Worcester Telegram & Gazette
- Louise Lind. "William Blackstone, Sage of the Wilderness",Blackstone Valley Tourism Council.