Born in 1644, the son of Admiral Sir William Penn, after whom he was named, William was raised in Wanstead, Essex where his father had built a country manor. Until the age of 12, William attended Archbishop Harsnett's School at Chigwell and around this time he had his first religious experience which profoundly affected his adult life. He became a convert to Quakerism (the Religious Society of Friends).

Although wealthy, William lived beyond his means. In order to raise funds he called in a debt owed to his father by King Charles II. On March 4, 1681 he obtained the charter for Pennsylvania. In August 1682 he gained the rights to Delaware from his friend James, Duke of York. William planned to make money by selling tracts of land, and although he was able to attract a good number of investors, he never realised the profits he had envisaged. More than 3,000 people flocked to the area in the first year.

However, he saw this venture as more than a money-making exercise; it was, in his famous words "an holy experiment." This experiment would become, as he confidently predicted, "the seed of a nation." William made religious tolerance a cornerstone of his administration of the colony.

Believing all people were equal, he treated the Indians with respect and tried to protect them from the ravages of rum and the rapacity of traders. In 1682 William is believed to have signed his famous treaty with the Delaware Indians at Shackamaxon (now Kensington, Philadelphia). The famous "wampum belt" allegedly given to him by the Indians is still in existence.

William returned to England to continue his dispute with Baltimore, not returning to Pennsylvania until 1699. London, England in the 1690s was a turbulent place, particularly for an outspoken, liberal Quaker. William never shirked from the political fray, as did many of his fellow Quakers, though his forthrightness proved dangerous. He supported James II, though in the revolution of 1688 when William and Mary came to the throne. Later, under suspicion of treason, William briefly lost control of his colony from 1692 to 1694. He received another setback when his wife died in 1694. He remarried within two years to Hannah Callowhill.

Back in Pennsylvania, political squabbling had set in and various leadership changes took place. In 1691 George Keith led a religious schism, and Pennsylvania and Delaware separated into two provinces. In 1696, William Markham's (William's secretary and then governor of Delaware) charter replaced the earlier 'Frame', though when William returned in 1701 he would again revise this version.

Although William's intention was to stay in America, perhaps retiring to his manor Pennsbury on the Delaware, further political troubles in England forced his return, and in 1712 he suffered a stroke which disabled him. His wife Hannah managed his affairs until the great man died in 1718. After Hannah's death in 1727 the proprietorship of Pennsylvania passed to their sons, John, Thomas, and Richard.