He was the eldest son of Sir James Whitelocke and Elizabeth Bulstrode, and was born on 6 August 1605 at George Croke's house in Fleet Street, London. He was baptized on 19 August 1605 at the nearby church of St Dunstan-in-the-West, where his mother's parents were married in 1571; his notorious uncle Edmund Whitelocke, being one of the godfathers, announced that the child was to be called Bulstrode. The vicar demurred, but Edmund insisted that he bear his mother's name, "Bulstrode or Elizabeth, let them choose which they please."  Bulstrode was educated briefly at Eton College, then at Merchant Taylors' School and at St John's College, Oxford, where he matriculated on 8 December 1620.
He left Oxford, without a degree, for the Middle Temple, and was called to the bar in 1626 and chosen treasurer of his Temple in 1628. He was fond of field sports and of music, and in 1633 he had charge of the music in the great masque performed by the Inns of Court before the king and queen. He was elected for Stafford in the parliament of 1626 and appointed recorder of Abingdon (1632-49), Oxford (1647-49), Bristol (1651-55) and counsel for Henley (1632). In 1640 he was chosen member for Great Marlow in the Long Parliament.
He took a prominent part in the proceedings against Strafford, was chairman of the committee of management, and had charge of articles XIX.-XXIV. of the impeachment. He drew up the bill for making parliaments indissoluble except by their own consent, and supported the Grand Remonstrance and the action taken in the House of Commons against the illegal canons; on the militia question, however, he advocated a joint control by king and parliament. On the outbreak of the English Civil War he took the side of the parliament, using his influence in the country as deputy-lieutenant to prevent the king's raising troops in Buckinghamshire and Oxfordshire.
He was sent to the king at Oxford both in 1643 and 1644 to negotiate terms, and the secret communications with Charles on the latter occasion were the foundation of a charge of treason brought against Whitelocke and Denzil Holles later. He was again one of the commissioners at the Treaty of Uxbridge in 1645.
Nevertheless, he opposed the policy of Holles and the peace party and the proposed disbanding of the army in 1647, and though one of the lay members of the assembly of divines, repudiated the claims of divine authority put forward by the Presbyterians for their church, and approved of religious tolerance. He thus gravitated more towards Oliver Cromwell and the army party, but he took no part either in the disputes between the army and the parliament or in the trial of the king. On the establishment of the Commonwealth, though out of sympathy with the government, he was nominated to the council of state and a commissioner of the Parliaments new Great Seal (1659-60).
Whitelocke purchased Greenlands House, Berkshire in 1651. The purchase of this land resulted in Whitelocke owning 3 miles of Thames water front below Henley On Thames. The site is now the home of Henley Business School, part of University of Reading.
He urged Cromwell after the Battle of Worcester and again in 1652 to recall the royal family, while in 1653 he disapproved of the expulsion of the Long Parliament and was especially marked out for attack by Cromwell in his speech on that occasion. Later in the autumn, and perhaps in consequence, Whitelocke was despatched on a mission to Christina, queen of Sweden, to conclude a treaty of alliance and assure the freedom of the Sound. Retroactively, the diplomatic mission caused him to be considered as the first of the English and British Ambassadors to Sweden, though at the time this was not a regular or fixed position.
On his return he resumed his office as commissioner of the Great Seal, was appointed a commissioner of the treasury with a salary of 1000,[clarification needed] and was returned to the parliament of 1654 for each of the four constituencies of Bedford, Exeter, Oxford and Buckinghamshire, electing to sit for the latter constituency.
Whitelocke was a learned and a sound lawyer. He had hitherto shown himself not unfavourable to reform, having supported the bill introducing the use of English into legal proceedings, having drafted a new treason law, and set on foot some alterations in chancery procedure. A tract advocating the registering of title-deeds is attributed to him. But he opposed the revolutionary innovations dictated by ignorant and popular prejudices. He defeated the strange bill which sought to exclude lawyers from parliament; and to the sweeping and ill-considered changes in the court of chancery proposed by Cromwell and the council he offered an unbending and honorable resistance, being dismissed in consequence, together with his colleague Sir Thomas Widdrington, on 6 June 1654 from his commissionership of the Great Seal (see William Lenthall).
He still, however, remained on good terms with Cromwell, by whom he was respected; he took part in public business, acted as Cromwell's adviser on foreign affairs, negotiated the treaty with Sweden of 1656, and, elected again to the parliament of the same year as member for Buckinghamshire, was chairman of the committee which conferred with Cromwell on the subject of the Petition and Advice and urged the protector to assume the title of king. In December 1657 he became a member of the Cromwell's Other House.
On Richard Cromwell's assumption of the Protectorship he was reappointed a commissioner of the Great Seal, and had considerable influence during the former's short tenure of power. He returned to his place in the Long Parliament on its recall, was appointed a member of the council of state on 14 May 1659, and became president in August; and subsequently, on the fresh expulsion of the Long Parliament, he was included in the committee of safety which superseded the council. He again received the Great Seal into his keeping on the first of November. During the period which immediately preceded the Restoration he endeavoured to oppose George Monck's schemes, and desired Charles Fleetwood to forestall him and make terms with Charles, but in vain.
On the failure of his plans he retired to the country and awaited events. Whitelocke's career, however, had been marked by moderation and good sense throughout. The necessity of carrying on the government of the country somehow or other had been the chief motive of his adherence to Cromwell rather than any sympathy for a republic or a military dictatorship, and his advice to Cromwell to accept the title of king was doubtless tendered with the object of giving the administration greater stability and of protecting its adherents under the Statute of Henry VII. Nor had he shown himself unduly ambitious or self-seeking in the pursuit of office, and he had proved himself ready to sacrifice high place to the claims of professional honour and duty. These considerations were not without weight with his contemporaries at the Restoration. Accordingly, Whitelocke was not excepted from the Act of Indemnity, and after the payment of various sums to the king and others he was allowed to retain the bulk of his property.
Whitelocke lived at Fawley Court in Buckinghamshire which he had inherited from his father in 1632. After the house was damaged during the Civil War he gave it to his son James and lived henceforth in seclusion at Chilton Lodge near Chilton Foliat in Wiltshire, dying on 28 July 1675.
He had married:
1. Rebecca, daughter of Thomas Bennet, by whom he had several children, including his eldest son James (died 1701);
3. Mary Carleton, daughter of Bigley Carleton, and widow of Rowland Wilson, by whom he had at least two sons, Samuel and Carleton.
Whitelocke was the author of: