On 23 April 1445, Margaret married King Henry VI of England, at Titchfield Abbey in Hampshire. Henry was eight years older than she was. The king and queen of France were the uncle and aunt of the groom and the bride respectively: Henry's late mother, Catherine, had been the sister of King Charles VII, whose wife Marie of Anjou was a sister of Margaret's father René. Further, Henry claimed for himself the Kingdom of France. He also controlled parts of northern France. Due to all this, the French king agreed to the marriage of Margaret to his rival on the condition that he would not have to provide the customary dowry and instead would receive the lands of Maine and Anjou from the English. The English government, fearing a highly negative reaction, kept this provision secret from the English public.
Margaret was crowned Queen Consort of England on 30 May 1445 at Westminster Abbey by John Stafford, Archbishop of Canterbury at the age of fifteen. She was described as beautiful, and furthermore "already a woman: passionate and proud and strong-willed". Those that anticipated the future return of English claims to French territory believed that she already understood her duty to protect the interests of the Crown fervently. She seems to have inherited this indomitability from her mother, who fought to establish her husband's claim to the Kingdom of Naples, and from her paternal grandmother Yolande of Aragon, who actually governed Anjou "with a man's hand", putting the province in order and keeping out the English. Thus by family example and her own forceful personality, she was fully capable of becoming the "champion of the Crown".
Henry was more interested in religion and learning than in military matters and was not a successful king. He had reigned since he was only a few months old. Many of his actions had been done by people who ruled in his place. When he married Margaret, his mental condition was already unstable. At the time their only son, Edward of Westminster, Prince of Wales was born (on 13 October 1453), Henry had already suffered a complete breakdown. There were rumours that he was incapable of fathering a child and that the new Prince of Wales was the result of an adulterous liaison. Many have speculated that either Edmund Beaufort, 2nd Duke of Somerset, or James Butler, 5th Earl of Ormond was the young prince's actual father. Both were faithful allies of Margaret.
Although Margaret was aggressively partisan and had a volatile temperament, she shared her husband's love of learning because of her cultured upbringing. She also gave her patronage to the founding of Queens' College, Cambridge.
Elizabeth Woodville (born ca 1437), later Queen of England as future wife of Margaret's husband's rival, King Edward IV, purportedly served Margaret of Anjou as a maid of honour. However, there is to little evidence to permit historians to establish this with absolute certainty: several women at Margaret's court bore the name Elizabeth or Isabella Grey.
After retiring from London to live in lavish state at Greenwich, Margaret was occupied with the care of her young son and did not display any signs of political will until she believed her husband was threatened with deposition by the ambitious Richard of York, 3rd Duke of York, who, to her consternation, had been appointed Lord Protector while Henry was mentally incapacitated from 1453 to 1454. The duke was a credible claimant to the English throne and by the end of his protectorship there were many powerful nobles and relatives prepared to back his claim. The Duke of York was powerful; Henry's advisers corrupt; Henry himself trusting, pliable, and increasingly unstable; Margaret defiantly unpopular, grimly and gallantly determined to maintain the English crown for her progeny. Yet at least one scholar identifies the source of the eventual Lancastrian downfall not as York's ambitions nearly so much as Margaret's ill-judged enmity toward York and her over-indulgence in unpopular allies. Nevertheless, Queen Margaret was a powerful force in the world of politics. King Henry was putty in her hands when she wanted something done.
Margaret's biographer Helen Maurer, however, disagrees with earlier historians having dated the much-vaunted enmity between the Queen and York to the time he obtained the office of the protectorship. She suggests the mutual antagonism came about two years later in 1455 in the wake of the First Battle of St Albans, when Margaret perceived him as a challenge to the king's authority. Maurer bases this conclusion on a judicious study of Margaret's pattern of presenting gifts; this revealed that Margaret took a great deal of care to demonstrate that she favoured both York and Edmund Beaufort (Somerset) equally in the early 1450s. Maurer also claims that Margaret appeared to accept York's protectorship and asserts there is no substantial evidence to back up the long-standing belief that she was responsible for the Yorkists' exclusion from the Great Council following Henry's recovery (see below).
The late historian Paul Murray Kendall, on the other hand, maintained that Margaret's allies Edmund Beaufort (Somerset) and William de la Pole, then Earl of Suffolk, had no difficulty in persuading her that York, until then one of Henry VI's most trusted advisers, was responsible for her unpopularity and already too powerful to be trusted. Margaret not only convinced Henry to recall York from his post as governor in France and banish him instead to Ireland, she repeatedly attempted to have him assassinated during his travels to and from Ireland, once in 1449 and again in 1450. Edmund Beaufort (Somerset) and Suffolk's joint responsibility for the secret surrender of Maine in 1448, and then the subsequent disastrous loss of the rest of Normandy in 1449 embroiled Margaret and Henry's court in riots, uprisings by the magnates, and calls for the impeachment and execution of Margaret's two strongest allies. It also might have made an ultimate battle to the death between Margaret and the House of York inevitable by making manifest Richard's dangerous popularity with the Commons. Richard of York, safely returned from Ireland in 1450, confronted Henry and was readmitted as a trusted advisor. Soon thereafter, Henry agreed to convene Parliament to address the calls for reform. When Parliament met, the demands could not have been less acceptable to Margaret: not only were both Edmund Beaufort (Somerset) and Suffolk impeached for criminal mismanagement of French affairs and subverting justice, but it was charged as a crime against Suffolk (now a duke) that he had antagonised the king against the Duke of York. Further, the demands for reform put forward included that the Duke of York be acknowledged as the first councillor to the king, and the Speaker of Commons, perhaps with more fervour than wisdom, even proposed Richard, Duke of York, be recognised as heir to the throne. Within a few months, however, Margaret had regained control of Henry, Parliament was dissolved, the incautious Speaker thrown in prison, and Richard of York retired to Wales for the time being.
In 1457, the kingdom was again outraged when it was discovered that Pierre de Brézé, a powerful French general and an adherent of Margaret, had landed on the English coast and burnt the town of Sandwich. As leader of a French force of 4,000 men from Honfleur, he aimed at taking advantage of the chaos in England. The mayor, John Drury, was killed in this raid. It thereafter became an established tradition, which survives to this day, that the Mayor of Sandwich wears a black robe mourning this ignoble deed. Margaret, in association with de Brézé, became the object of scurrilous rumours and vulgar ballads. Public indignation was so high that Margaret, with great reluctance, was forced to give the Duke of York's kinsman Richard Neville, 16th Earl of Warwick, a commission to keep the sea for three years. He already held the post of Captain of Calais.