Educated at Brasenose College, Oxford and at the Inns of Court. He was elected MP for Cheshire in 1628, where his seat was Handforth Hall. He worked hard to increase the value of his estates. For example he was interested in field sports and built a duck decoy at Dodleston which became something of a commercial operation.
In the summer of 1634 he visited Holland and the Seventeen Provinces and wrote a detailed account of his travels. He took a keen interest in military matters and studied siege warfare there at first hand. In the following year from June 11 to August 4 he journeyed through north eastern England to lowland Scotland and thence to Ireland, returning to land in England at Minehead from where he made his way back to Chester. In other years he journeyed in France and other parts of England although his records of the journeys have been lost.
Re-elected to Parliament in 1640, he took a stand against King Charles I. In 1642, he joined the Parliamentarian forces, and in March 1643 was appointed Commander-in-Chief for Parliament's army in Cheshire, where he quickly established a formidable intelligence network of spies and agents. He defeated the Royalists at the First Battle of Middlewich on March 13 and established his Cheshire headquarters at Nantwich. In 1643, when Parliament's cause floundered elsewhere, Brereton stood out as a success, establishing Parliamentary dominance in Cheshire. With success came attention from the Royalists. More Cavaliers entered Cheshire to counter Brereton's forces and in late 1643 he suffered his only major defeat at the Second Battle of Middlewich. The Royalists were unable to press home the initiative however and in January 1644 Lord Byron's Royalists were routed by Sir Thomas Fairfax and Brereton at the Battle of Nantwich.
After a spell in London, Brereton returned to Cheshire. He was one of three officers (the other two being Sir Thomas Middleton (soldier) and Oliver Cromwell) specifically exempted by Parliament from the provisions of the Self-denying Ordinance. Brereton turned his attentions to besieging Chester, a Royalist stronghold. Byron, now governor of the city, held out until February 1646, but finally had to capitulate. Brereton played an important role in the first civil war's final major pitched Battle at Stow-on-the-Wold, but thereafter faded into the background vis-a-vis military matters. He continued in politics however.
A series of letter books survive in which he preserved copies of letters he wrote, especially during the English Civil War.
Sir William Brereton married as his first wife Susanna, daughter of Sir George Booth of Dunham Massey, Baronet. By her Brereton had Sir Thomas, his only son and successor as Baronet, and three daughters: Frances, wife of Edward Ward, 10th Baron Dudley and 2nd Baron Ward; Susanna, who married Edmund Lenthall, son of Sir John Lenthall; and Catherine, who died unmarried. Brereton's second wife was Cicely, daughter of Sir William Skeffington, Baronet of Staffordshire. They had a daughter, Cicely, who became the wife of Edward, 4th Earl of Meath.
In 1699, a family dispute broke out between these heirs, when Susanna Brereton's daughter Mary, who had married John Levett Esq. of the Inner Temple, London, petitioned the House of Lords in London on behalf of Edward Ward, 11th Baron Dudley and 3rd Baron Ward, who was an infant when his father died, and whose guardianship had been held by Edward, Earl of Meath, and his wife, who was the aunt of the infant lord.