Thutmose III was born into the Eighteenth Dynasty as the son of Thutmose II and a secondary wife named Iset. When his father died around 1479 BCE, the heir was still a child. Hatshepsut, the dead king's principal queen and Thutmose III's stepmother, first governed as regent and then adopted the full titles of a pharaoh, ruling as the senior king while the boy remained a junior monarch. The surviving evidence does not show him imprisoned or removed from public life. He appeared in royal scenes, received the education expected of a prince, and probably gained the military experience that later made him such an effective commander. After roughly twenty-one years of shared rule, Hatshepsut died, and Thutmose III continued alone for more than three decades.

His first great test as sole ruler came almost immediately. A coalition of Levantine rulers led by the king of Kadesh gathered at Megiddo, hoping the change of power in Egypt would bring independence. The Annals carved at Karnak preserve an unusually detailed account of the campaign. When Thutmose reached Yehem, his officers advised him to avoid the narrow Aruna pass and take one of two safer roads around Mount Carmel. The king chose the dangerous central route, sending his force through a defile where men and horses had to advance in a stretched column. The risk created surprise. The Egyptian army emerged close to Megiddo, defeated the coalition in open battle, and then besieged the city after its defenders escaped behind the walls. The victory restored Egyptian authority in northern Canaan and gave Thutmose a base for later campaigns.

Megiddo was only the beginning. Thutmose III carried out at least seventeen major military expeditions into Palestine, Syria, and Nubia. Some were campaigns of conquest, while others collected tribute, suppressed rebellion, or reinforced earlier gains. In his eighth campaign, during his thirty-third regnal year, he crossed the Euphrates during operations against Mitanni and commemorated the achievement near the boundary stela raised there by his grandfather Thutmose I. In the south, Egyptian control extended to the Fourth Cataract of the Nile. The empire that emerged linked Egypt to Canaan, the Syrian coast, Nubia, and the diplomatic world of the great Near Eastern kingdoms, bringing captives, horses, metals, luxury goods, and regular tribute into the royal economy.

The king presented these victories as gifts from Amun, the state god whose temple at Karnak stood at the centre of royal power. The campaign records were eventually carved on the temple walls, setting out expeditions, captured towns, tribute, and offerings made to the god. Military control was supported by administration as well as force. Egyptian officials, garrisons, and loyal local rulers helped maintain the territories, while the sons of foreign princes could be brought to Egypt, educated at court, and returned as rulers tied to the pharaoh. Thutmose also prepared his own succession by elevating his son Amenhotep II near the end of the reign, preventing the child-king crisis that had shaped his own youth.

Thutmose III built or restored temples across Egypt and Nubia, but his most distinctive monument was the Akh-menu, the Festival Hall of Thutmose III, in the precinct of Amun-Re at Karnak. Its king list placed him within the authorised line of earlier rulers, while a chamber often called the botanical garden displayed carved plants and animals encountered in foreign lands. These reliefs reveal that conquest was represented not only through prisoners and weapons but also through the collection and ordering of the natural world. The king's building programme, supported by imperial wealth, made Karnak a record of his military, religious, and intellectual ambitions.

The relationship between Thutmose III and Hatshepsut remained complicated even after her death. Her monuments were not attacked immediately. The removal of some names and royal images began much later in his reign, when the succession of Amenhotep II had become a pressing concern. The motive is still debated: personal resentment cannot be proved, and the delayed, selective changes may instead have been intended to strengthen a direct male line from Thutmose I through Thutmose II and Thutmose III to Amenhotep II. Whatever the reason, Hatshepsut's memory was damaged, while the junior king she had once overshadowed became the dominant military figure of the dynasty.

Thutmose III died around 1425 BCE after fifty-four regnal years, a total that included the long co-rule with Hatshepsut. He was buried in KV34, a tomb cut high in the Valley of the Kings and reached by a steep approach. Its burial chamber contained a cartouche-shaped stone sarcophagus, and its walls preserved a complete version of the Amduat, the guide to the sun god's twelve-hour journey through the night, drawn in a spare style resembling figures on papyrus. Priests later moved the mummy to the Deir el-Bahri royal cache for protection. His reputation survived far beyond the New Kingdom: the throne name Menkheperre continued to appear on scarabs and amulets centuries after his death, evidence that later Egyptians remembered him not only as a conqueror but as a powerful and protective royal name.