Baron William Cecil Burghley, (1521-1508), was born, according to his own statement, on the 13th of September 1521 at the house of his mother's father at Bourne, Lincolnshire. Pedigrees, elaborated by Cecil himself with the help of Camden, the antiquary, associated him with the Cecils or Sitsyllts of Altyrennes in Herefordshire, and traced his descent from an Owen of the time of King Harold and a Sitsyllt of the reign of Rufus. The connexion with the Herefordshire family is not so impossible as the descent from Sitsyllt; but the earliest authentic ancestor of the lord treasurer is his grandfather, David, who, according to Burghley's enemies, "kept the best inn" in Stamford. David somehow secured the favour of Henry VII., to whom he seems to have been yeoman of the guard. He was serjeant-at-arms to Henry VIII. in 1526, sheriff of Northamptonshire in 1532, and a justice of the peace for Rutland. His eldest son, Richard, yeoman of the wardrobe (d. 1554), married Jane, daughter of William Heckington of Bourne, and was father of three daughters and Lord Burghley.

William, the only son, was put to school first at Grantham and then at Stamford. In May 1535, at the age of fourteen, he went up to St John's College, Cambridge, where he was brought into contact with the foremost educationists of the time, Roger Ascham and John Cheke, and acquired an unusual knowledge of Greek. He also acquired the affections of Cheke's sister, Mary, and was in 1541 removed by his father to Gray's Inn, without, after six years' residence at Cambridge, having taken a degree. The precaution proved useless, and four months later Cecil committed one of the rare rash acts of his life in marrying Mary Cheke. The only child of this marriage, Thomas, the future earl of Exeter, was born in May 1542, and in February 1543 Cecil's first wife died. Three years later he married (21st of December 1546) Mildred, daughter of Sir Anthony Cooke, who was ranked by Ascham with Lady Jane Grey as one of the two most learned ladies in the kingdom, and whose sister, Anne, became the wife of Sir Nicholas, and the mother of Sir Francis, Bacon.

Cecil, meanwhile, had obtained the reversion to the office of custos rotulorum brevium, and, according to his autobiographical notes, sat in parliament in 1543; but his name does not occur in the imperfect parliamentary returns until 1547, when he was elected for the family borough of Stamford. Earlier in that year he had accompanied Protector Somerset on his Pinkie campaign, being one of the two "judges of the Marshalsea," i.e. in the courts-martial. The other was William Patten, who states that both he and Cecil began to write independent accounts of the campaign, and that Cecil generously communicated his notes for Patten's narrative, which has been reprinted more than once.

In 1548 he is described as the protector's master of requests, which apparently means that he was clerk or registrar of the court of requests which the protector, possibly at Latimer's instigation, illegally set up in Somerset House "to hear poor men's complaints." He also seems to have acted as private secretary to the protector, and was in some danger at the time of the protector's fall (October 1549). The lords opposed to Somerset ordered his detention on the 10th of October, and in November he was in the Tower. On the 25th of January 1550 he was bound over in recognizances to the value of a thousand marks. However, he soon ingratiated himself with Warwick, and on the 15th of September 1550 he was sworn one of the king's two secretaries. He was knighted on the 11th of October 1551, on the eve of Somerset's second fall, and was congratulated on his success in escaping his benefactor's fate. In April he became chancellor of the order of the Garter. But service under Northumberland was no bed of roses, and in his diary Cecil recorded his release in the phrase ex misero aulico factus liber et mei juris. His responsibility for Edward's illegal "devise" of the crown has been studiously minimized by Cecil himself and by his biographers.

Years afterwards, he pretended that he had only signed the "devise" as a witness, but in his apology to Queen Mary he did not venture to allege so flimsy an excuse; he preferred to lay stress on the extent to which he succeeded in shifting the responsibility on to the shoulders of his brother-in-law, Sir John Cheke, and other friends, and on his intrigues to frustrate the queen to whom he had sworn allegiance. There is no doubt that he saw which way the wind was blowing, and disliked Northumberland's scheme; but he had not the courage to resist the duke to his face. As soon, however, as the duke had set out to meet Mary, Cecil became the most active intriguer against him, and to these efforts, of which he laid a full account before Queen Mary, he mainly owed his immunity. He had, moreover, had no part in the divorce of Catherine or in the humiliation of Mary in Henry's reign, and he made no scruple about conforming to the religious reaction. He went to mass, confessed, and out of sheer zeal and in no official capacity went to meet Cardinal Pole on his pious mission to England in December 1554, again accompanying him to Calais in May 1555. It was rumoured in December 1554 that Cecil would succeed Sir William Petre as secretary, an office which, with his chancellorship of the Garter, he had lost on Mary's accession.

Probably the queen had more to do with the falsification of this rumour than Cecil, though he is said to have opposed in the parliament of 1555 - in which he represented Lincolnshire - a bill for the confiscation of the estates of the Protestant refugees. But the story, even as told by his biographer (Peck, Desiderata Curiosa, i. 11), does not represent Cecil's conduct as having been very courageous; and it is more to his credit that he found no seat in the parliament of 1558, for which Mary had directed the return of "discreet and good Catholic members."