Born into the Welsh gentry, Jeffreys was admitted to the bar in 1668, and in 1677 he obtained an appointment as solicitor general to Charles II's Roman Catholic brother James, duke of York (later James II). During the panic that followed Titus Oates's fabricated revelations (1678) of a popish plot against the government, Jeffreys served as a prosecuting counsel or judge in many of the trials of suspected Catholic conspirators. He earned notoriety by savagely ridiculing and bullying the defendants.

Despite his Protestantism and his role as a prosecutor of Catholics, Jeffreys became increasingly prominent in the court party of Charles and James. In 1680 he fought against the Exclusion Bill, which would have prevented James from succeeding to the throne, and in 1683 he became lord chief justice. Meanwhile, he served as prosecutor and judge, respectively, in the treason trials of Lord William Russell and Algernon Sidney. Although the evidence against these two Whig defendants was flimsy, Jeffreys had them convicted and executed. He sentenced Titus Oates to a severe flogging and imprisonment in May 1685, and in the same month James II made him Baron Jeffreys of Wem.

During the “Bloody Assizes” that followed the collapse (July 1685) of the insurrection of James Scott, duke of Monmouth, Jeffreys prosecuted the rebels with ferocity, executing perhaps 150 to 200 persons and ordering hundreds of others sold into slavery in the colonies. At the same time, he profited by extorting money from the victims. Nevertheless, James II made him lord chancellor in September 1685. As one of the most influential royal advisers, Jeffreys took charge of the ecclesiastical commission that forced the Church of England to accept James's pro-Catholic policies. When William of Orange, stadholder of Holland (later King William III), overthrew James's government in December 1688, Jeffreys tried to escape from the country disguised as a sailor, but he was arrested and died four months later in the Tower of London.