His father was captured at the Battle of Pavia in 1525 by his sworn enemy, Charles V, Holy Roman Emperor, and held prisoner in Spain. To obtain his release it was eventually agreed that Henry and his older brother be sent to Spain in his place. They remained in captivity for three years.

Henry married Catherine de' Medici (13 April 1519 – 5 January 1589) on 28 October 1533, when they were both fourteen years old. The following year, he became romantically involved with a thirty - five year old widow, Diane de Poitiers. They had always been very close: she had publicly embraced him on the day he set off to Spain, and during a jousting tournament, he insisted his lance carry her ribbon instead of his wife's. Diane became Henry's most trusted confidante and, for the next twenty - five years, wielded considerable influence behind the scenes, even signing royal documents. Extremely confident, mature and intelligent, she left Catherine powerless to intervene. She did, however, insist that Henry sleep with Catherine in order to produce heirs to the throne.

When his elder brother, Francis, died in 1536 after a game of tennis, Henry became heir to the throne. He succeeded his father on his 28th birthday and was crowned King of France on 25 July 1547 at Cathedral of Notre - Dame in Reims.

Henry's reign was marked by wars with Austria, and the persecution of the Protestant Huguenots. Henry II severely punished them, particularly the ministers: burning them at the stake or cutting off their tongues for uttering heresies. Even those only suspected of being Huguenots could be imprisoned. The Edict of Châteaubriant (27 June 1551) called upon the civil and ecclesiastical courts to detect and punish all heretics and placed severe restrictions on Huguenots, including the loss of one third of their property to informers, and confiscations. It also strictly regulated publications by prohibiting the sale, importation or printing of any unapproved book. It was during the reign of Henry II that Huguenot attempts at establishing a colony in Brazil were made, with the short lived formation of France Antarctique.

The Italian War of 1551 – 1559, sometimes known as the Hapsburg – Valois War, began when Henry declared war against Charles V with the intent of recapturing Italy and ensuring French, rather than Habsburg, domination of European affairs. Henry II allied with German Protestant princes at the Treaty of Chambord in 1552. Simultaneously, the continuation of his father's Franco - Ottoman alliance allowed Henry II to push for French conquests towards the Rhine while a Franco - Ottoman fleet defended southern France. An early offensive into Lorraine was successful, with Henry capturing the three episcopal cities of Metz, Toul, and Verdun, and securing them by defeating the Habsburg army at the Battle of Renty in 1554. However the attempted French invasion of Tuscany in 1553 was defeated at the Battle of Marciano.

After Charles's abdication in 1556 split the Habsburg empire between Philip II of Spain and Ferdinand I, the focus of the war shifted to Flanders, where Phillip, in conjunction with Emmanuel Philibert of Savoy, defeated the French at St. Quentin. England's entry into the war later that year led to the French capture of Calais, and French armies plundered Spanish possessions in the Low Countries. Henry was nonetheless forced to accept the Peace of Cateau - Cambrésis, in which he renounced any further claims to Italy.

The Peace of Cateau - Cambrésis was signed between Elizabeth I of England and Henry on 2 April and between Henry and Philip II of Spain on 3 April 1559 at Le Cateau - Cambrésis, around twenty kilometers southeast of Cambrai. Under its terms, France restored Piedmont and Savoy to the Duke of Savoy, but retained Saluzzo, Calais and the bishoprics of Metz, Toul, and Verdun. Spain retained Franche - Comté. Emmanuel Philibert, Duke of Savoy, married Margaret of France, Duchess of Berry, the sister of Henry II, and Philip II of Spain married Henry's daughter Élisabeth.

Henry raised the young Mary, Queen of Scots, at his court, hoping to use her ultimately to establish a dynastic claim to Scotland. On 24 April 1558, Henry's fourteen year old son Francis was married to Mary in a union intended to give the future king of France not only the throne of Scotland but a claim to the throne of England. Henry had Mary sign secret documents, illegal in Scottish law, that would ensure Valois rule in Scotland even if she died without an heir. Mary's claim to the English throne quickly became an issue when Mary I of England died later in 1558, Henry and his Catholic advisers regarding Elizabeth I unfit to reign because of her illegitimacy.

Henry II introduced the concept of publishing the description of an invention in the form of a patent. The idea was to require an inventor to disclose his invention in exchange for monopoly rights to the patent. The description is called a patent “specification”. The first patent specification was submitted by the inventor Abel Foullon for "Usaige & Description de l'holmetre" (a type of rangefinder). Publication was delayed until after the patent expired in 1561.

Henry II was an avid hunter and a participant in jousts and tournaments. On 30 June 1559, at the Place Royale, during a match to celebrate the Peace of Cateau - Cambrésis with his longtime enemies, the Habsburgs of Austria, and to celebrate the marriage of his daughter Elisabeth of Valois to King Philip II of Spain, King Henry was mortally wounded by the lance of Gabriel Montgomery, captain of the King's Scottish Guard. The lance pierced his eyes and, despite the efforts of royal surgeon Ambroise Paré, he died on 10 July 1559 from septicaemia. He was buried in a cadaver tomb in Saint Denis Basilica. Henry's death was a factor in the end of jousting as a sport.

As Henry lay dying, Queen Catherine limited access to his bedside and denied his mistress Diane de Poitiers access to him, even though he repeatedly asked for her. Following his death, Catherine sent Diane into exile, where she lived in comfort on her own properties until her death.

Henry was succeeded by his son, Francis II, who died the following year and was succeeded by his two brothers. Their mother acted as Regent. For the forty years following Henry II's death, France was filled with turbulence as Protestants and Catholics fought the bitter French Wars of Religion.

Nostradamus, a French astrological writer known for his prophecies, is often said to have become famous when one of his quatrains was construed as a prediction of the death of King Henry II:

CI, Q 35 The young lion shall overcome the older one,
on the field of combat in single battle,
He shall pierce his eyes in a golden cage,
Two forces one, then he shall die a cruel death.

But, in fact, the link was first proposed in print only in 1614, fifty - five years after the event and forty - eight after Nostradamus' death; thus it qualifies as a postdiction, or vaticinium ex eventu. The Italian astrologer Luca Gaurico, a contemporary of Nostradamus, is also said to have predicted the king's death.