In 1528, sweating sickness broke out with great severity. In London, the mortality rate was great and the court was dispersed. Henry left London, frequently changing his residence; Anne Boleyn retreated to the Boleyn residence Hever Castle, but contracted the illness; her brother-in-law, William Carey, died. Henry sent his own physician to Hever Castle to care for her, and shortly afterwards, she recovered. It soon became the one absorbing object of Henry's desires to secure an annulment from Catherine. Henry set his hopes upon a direct appeal to the Holy See, acting independently of Cardinal Wolsey, to whom he at first communicated nothing of his plans related to Anne. William Knight, the King's secretary, was sent to Pope Clement VII to sue for the annulment of his marriage to Catherine, on the grounds that the dispensing bull of Pope Julius II was obtained by false pretences. Henry also petitioned, in the event of his becoming free, a dispensation to contract a new marriage with any woman even in the first degree of affinity, whether the affinity was contracted by lawful or unlawful connection. This clearly referred to Anne.

As the Pope was, at that time, prisoner of Charles V, the Holy Roman Emperor, as a result of the Sack of Rome in May 1527, Knight had some difficulty obtaining access. In the end, he had to return with a conditional dispensation, which Wolsey insisted was technically insufficient. Henry had now no choice but to put his great matter into the hands of Wolsey, who did all he could to secure a decision in Henry's favour. Wolsey went so far as to convene an ecclesiastical court in England, with a special emissary from the Pope himself, to decide the matter. But the Pope never had empowered his deputy to make any decision. The Pope was still a veritable hostage of Charles V, and Charles V was the loyal nephew of Henry's queen, Catherine. The Pope forbade Henry to contract a new marriage until a decision was reached in Rome, not in England. Convinced Wolsey's loyalties lay with the Pope, not England, Anne and Wolsey's many enemies ensured his dismissal from public office in 1529, when Henry finally agreed to his arrest on grounds of praemunire. Had it not been for his death from illness in 1530, he might have been executed for treason. A year later, Queen Catherine was banished from court and her rooms were given to Anne.

Public support, however, remained with Queen Catherine. One evening in the autumn of 1531, Anne was dining at a manor house on the river Thames and was almost seized by a crowd of angry, hostile women. Anne just managed to escape by boat.

When Archbishop of Canterbury William Warham died in 1532, the Boleyn family chaplain, Thomas Cranmer, was appointed, with papal approval.

In 1532 Thomas Cromwell brought before Parliament a number of acts including the Supplication against the Ordinaries and Submission of the Clergy, which recognised royal supremacy over the church, thus finalizing the break with Rome. Following these acts, Thomas More resigned as Chancellor, leaving Cromwell as Henry's chief minister.

Anne Boleyn often acted independently of her future husband, able to grant petitions, receive diplomats, preside over patronage appointments and foreign policy. The ambassador from Milan wrote in 1531 that it was essential to have her approval if one wanted to influence the English government, a view corroborated by an earlier French ambassador, in 1529.

During this period, Anne Boleyn did indeed play an important role in England's international position by solidifying an alliance with France. She established an excellent rapport with the French ambassador, Gilles de la Pommeraie. Anne and Henry attended a meeting with the French king at Calais in winter 1532, in which Henry hoped to enlist the support of Francis I of France for his intended marriage. Henry endowed his future wife with an appropriate rank. On 1 September 1532, she was created Marquess of Pembroke, and became the most prestigious non-royal woman in the realm. The Pembroke title was significant for the Tudor family because Henry's great-uncle, Jasper Tudor, had held the title of Earl of Pembroke; and Henry performed the investiture himself.

Anne's family also profited from the relationship. Her father, already Viscount Rochford, was created Earl of Wiltshire. Henry also came to an arrangement with Anne's Irish cousin and created him Earl of Ormond. At the magnificent banquet to celebrate her father's elevation, Anne took precedence over the Duchesses of Suffolk and Norfolk, seated in the place of honour beside the King which was usually occupied by the Queen. Thanks to Anne's intervention, her widowed sister Mary received an annual pension of £100, and Mary's son, Henry Carey, was educated at a prestigious Cistercian monastery.

The conference at Calais was something of a political triumph, but, although the French government gave implicit support for Henry's re-marriage and Francis I himself held private conference with Anne, the French King maintained alliances with the Pope which he could not explicitly defy. Soon after returning to Dover, Henry and Anne married in a secret ceremony. She soon became pregnant and, as was the custom with royalty, there was a second wedding service, likewise shrouded in secrecy, which took place in London on 25 January 1533. Events now began to move at a quick pace. On 23 May 1533, Cranmer (who had been hastened, with the Pope's assent, into the position of Archbishop of Canterbury recently vacated by the convenient death of Warham) sat in judgment at a special court convened at Dunstable Priory to rule on the validity of the King's marriage to Catherine of Aragon. He thereupon declared the marriage of Henry and Catherine null and void. Five days later, on 28 May 1533, Cranmer declared the marriage of Henry and Anne to be good and valid.