Talbot was a godson of King Charles II, after whom he was named, and he was brought up as a Roman Catholic, but in 1679 under the influence of John Tillotson he became a member of the Church of England.
On his father's death he succeeded to the Earldom of Shrewsbury, received an appointment in the household of Charles II, and served in the army under James II. Nonetheless, in 1687 he was in correspondence with the Prince of Orange, and he was one of the seven signatories of the letter of invitation to William in the following year. He contributed towards defraying the expenses of the projected invasion, and having crossed to Holland to join William, he landed with him in England in November 1688 during the Glorious Revolution.
Shrewsbury became Secretary of State for the Southern Department in the first administration of William and Mary, but he resigned office in 1690 when the Tories gained the upper hand in parliament. While in opposition he brought forward the Triennial Bill, to which the King refused assent. In 1694 he again became Secretary of State; but there is some evidence that as early as 1690, when he resigned, he had gone over to the Jacobites and was in correspondence with James at his court in exile at Saint-Germain-en-Laye, though it has been stated on the other hand that these relations were entered upon with William's connivance for reasons of policy.
However this may be, William appears to have had no suspicion of Shrewsbury's loyalty, for on 30 April 1694 the latter was created Marquess of Alton and Duke of Shrewsbury, and he acted as one of the regents during the King's absence from England in the two following years. In 1696 definite accusations of treason were brought against him by Sir John Fenwick, which William himself communicated to Shrewsbury; and about this time the Secretary of State took but a small part in public business, again professing his anxiety to resign. His plea of ill-health was a genuine one, and in 1700 the king reluctantly consented to his retirement into private life.
For the next seven years Shrewsbury lived abroad, chiefly at Rome, whence in 1701 he wrote a celebrated letter to Lord Somers expressing his abhorrence of public life and declaring that if he had a son he "would sooner bind him to a cobbler than a courtier, and a hangman than a statesman."
On the accession of Queen Anne the Whig leaders made an ineffectual attempt to persuade Shrewsbury to return to office. When he returned at last to England in 1707, he gradually became alienated from his old political associates, and in 1710 he accepted the post of Lord Chamberlain in the Tory administration, to which the queen appointed him without the knowledge of Godolphin and Marlborough; his wife was at the same time made a Lady of the Bedchamber.
After a diplomatic mission to France for the purpose of negotiating preliminaries of peace, Shrewsbury became Lord Lieutenant of Ireland in 1713; but he was in London in July 1714 during the memorable crisis occasioned by the impending death of Queen Anne. On 29 July, when the queen was dying, the Earl of Oxford received his long-delayed dismissal from the office of Lord Treasurer. On July 30, Shrewsbury and other ministers assembled at Kensington Palace and, being admitted to the queen's bedchamber, Bolingbroke recommended the appointment of Shrewsbury to the vacant treasurership; Anne at once placed the staff of that high office in the duke's hands.
Thus, when the queen died on 1 August, Shrewsbury was in a position of supreme power with reference to the momentous question of the succession to the crown. He threw his influence into the scale in favor of the Elector of Hanover, and was powerfully influential in bringing about the peaceful accession of George I, and in defeating the design of the Jacobites to place the son of James II on the throne. His disinclination for the highest political offices remained, however, as great as before; and having resigned the lord-treasurership and the lord-lieutenancy of Ireland, he was appointed Lord Chamberlain. This place he resigned in July 1715, and he died on 1 February 1718.
The Duke of Shrewsbury was one of the greatest noblemen of the reign of Queen Anne. Though blind in one eye, he was strikingly handsome in person, his demeanour was dignified and his manners full of grace and courtesy. Swift described him as "the finest gentleman we have", and as "the favorite of the nation", while William III spoke of him as "the king of hearts". Like most of his contemporaries he endeavoured to keep himself in favor both with the exiled house of Stuart and with the reigning sovereign in England; but at the two critical junctures of 1688 and 1714 he acted decisively in favor of the Protestant succession. At other times he appeared weak and vacillating, and he never wholeheartedly supported either Whigs or Tories, though he co-operated with each in turn. His magnanimous disposition saved him from the vindictiveness of the party politician of the period; and the weak health from which he suffered through life probably combined with a congenital lack of ambition to prevent his grasping the power which his personality and talents might have placed in his hands.
In 1705 Shrewsbury married Adelaide Roffeni, daughter of the Marquis Andrea Paleotti and Christina Dudley Paleotti of Bologna. This lady, who is said to have had "a great many engaging qualities" besides many accomplishments, was the subject of much malicious gossip. She was the widow, or as some declared, the mistress of a Count Brachiano; and Lady Cowper reported that the lady's brother had forced Shrewsbury to marry her "after an intrigue together". After Shrewsbury's return to England the duchess became conspicuous in London society, where the caustic wit of Lady Mary Wortley Montagu was exercised at her expense. On the accession of George I the duchess of Shrewsbury became a lady of the bedchamber to the Princess of Wales, a position which she retained till her death on 29 June 1726. Shrewsbury left no children, and at his death the dukedom became extinct, the earldom of Shrewsbury passing to his cousin Gilbert Talbot.