He received his education at Charterhouse School and at Pembroke College, Oxford. In 1743 he was elected fellow of All Souls College, Oxford, and [he] was called to the bar as a barrister at the Middle Temple in 1746. After practicing in thecourts of Westminster for several years without great success, in 1753 he retired to Oxford where he launched a pioneering private lecture course on the laws and government of England (not then taught at either English university). In 1758 he was elected unopposed to the new chair in English Law endowed by the will of Charles Viner (who had died in 1756), delivering his first lecture as foundation Vinerian Professor on 25 October 1758. In 1761, Blackstone married Sarah Clitherow and had nine children. Blackstone was also appointed Principal of New Inn Hall (now St. Peter's College, Oxford), a position which he held until 1766. Blackstone lived at Priory Place (later Castle Priory) in Wallingford, and is buried at St Peter's Church in the town.

In 1761 Blackstone won election as a Member of Parliament for Hindon and received a patent of precedence at the bar (equivalent to the rank of king's counsel). Blackstone's "political views were those of the Old Whigs and his ideals were those of the Glorious Revolution of 1688". He was knighted in 1770 and appointed a puisne justice of the Court of Common Pleas.

The four volumes of the Commentaries, first published between 1765 and 1769 in Oxford and first issued in an American edition in 1771, won instant recognition for their able synthesis of the often bewildering doctrines that made up the common law and for their elegant writing style. Leading American attorneys who first learned their law by reading Blackstone include Alexander Hamilton and Abraham Lincoln. Thomas Jefferson at first admired Blackstone's learning and eloquence, but later denounced his treatise as "honeyed Mansfieldism," a reference to the great conservative English jurist Lord Mansfield.

In addition to the Commentaries, Blackstone published the first scholarly edition of Magna Carta and the Charter of the Forest. He also wrote poetry, numerous pamphlets on university and national politics, two architectural manuscripts, and other legal treatises. Blackstone and his work occasionally appear in literature. For example, Blackstone receives mention in Herman Melville's Moby-Dick. A passing reference to the Commentaries is also to be found in Francis Parkman's The Oregon Trail. A bust of Blackstone is a typical ornament of a lawyer's office in early Perry Mason novels, and in Anatomy of a Murder. Blackstone's Commentaries are also mentioned in Charles Portis's comic novel, The Dog of the South. It is also mentioned in Harper Lee's To Kill a Mockingbird as the tool used to teach Calpurnia, a black woman, how to read. Blackstone wrote his books on common law shortly before the American Declaration of Independence was written. Many terms and phrases, particularly the term Pursuit of Happiness, used by the framers were derived from Blackstone's works.

U.S. courts frequently quote Blackstone's Commentaries on the Laws of England as the definitive pre-Revolutionary War source of common law; in particular, the United States Supreme Court quotes from Blackstone's work whenever they wish to engage in historical discussion that goes back to the era of the nation's founding, to illuminate the legal and intellectual culture that helped to shape the intent of the Framers of the Constitution). His work has been used most forcefully as of late by Justice Clarence Thomas. U.S. and other common law courts mention with strong approval Blackstone's formulation also known as Blackstone's ratio popularly stated as "Better that ten guilty persons escape than that one innocent suffer" — although he did not first express the principle.

The Virginia lawyer and judge St. George Tucker prepared his own edition of Blackstone's Commentaries, adapting the treatise to American needs and conditions. His version was widely used for much of the nineteenth century.

Blackstone's work was more often synthetic than original, but his writing was organized, clear, and dignified, which brings his great work within the category of general literature. He also had a turn for neat and polished verse, of which he gave proof in The Lawyer's Farewell to his Muse.

Blackstone's characterization of property rights as "sole and despotic dominion which one man claims and exercises over the external things of the world, in total exclusion of the right of any other individual in the universe," has often been quoted in judicial opinions and secondary legal literature as the dominant Western concept of property. In spite of the frequency with which this conception is quoted, however, the phrase is often presented without taking into account the greater context of Blackstone's thought on the subject of property. Blackstone likely offered the statement as a rhetorical flourish to begin his discussion, given that even in his age, individual property rights were not sole and absolute.

William Blackstone's Commentaries summarized his attitude toward Roman Catholics as follows:

As to papists, what has been said of the Protestant dissenters would hold equally strong for a general toleration of them; provided their separation was founded only upon difference of opinion in religion, and their principles did not also extend to a subversion of the civil government. If once they could be brought to renounce the supremacy of the pope, they might quietly enjoy their seven sacraments, their purgatory, and auricular confession; their worship of reliques and images; nay even their transubstantiation. But while they acknowledge a foreign power, superior to the sovereignty of the kingdom, they cannot complain if the laws of that kingdom will not treat them upon the footing of good subjects.

:— Bl. Comm. IV, c.4 ss. iii.2, p. *54