The Hittites, who spoke an Indo-European language (a family of languages that includes English), dominated much of Anatolia and neighboring regions between about 1650 and 1200 B.C. It has been suggested that groups speaking languages related to Hittite first entered Anatolia at the end of the third millennium B.C., but the Hittites first rose to prominence around 1750 B.C., when King Pithana and his son Anitta captured the important city of Kanesh as well as a number of other city-states, including that of Hattusha (modern Bogazkšy).

Sometime around 1650 B.C., under Hattushili I, the city of Hattusha was established as the Hittite capital. Situated on a plateau, Hattusha was heavily fortified over time with elaborate defensive walls and gateways. From this secure base, Hattushili led his armies south onto the plains of Syria. His son, Murshili I, continued these advances by raiding the important city of Halab (Aleppo) and plundering Babylon far to the south in Mesopotamia. On his return to Anatolia, however, the king was assassinated and there followed a succession of weak rulers and a long period of inactivity. Around 1420 B.C., a new line of more energetic kings came to power in Hattusha. Nonetheless, the Hittites seem to have suffered considerable problems in the early fourteenth century B.C.: the so-called Gashga people, who lived in the Pontic Alps to the north of Hittite territory, launched raids and may even have destroyed Hattusha; the dominant power of Egypt under Amenhotep III (r. 1390–1352 B.C.) attempted to undermine the Hittites by establishing diplomatic relations with the powerful state of Arzawa in western Anatolia; and raids against Cyprus (claimed by the Hittites as their territory) were undertaken by Ahhiyawa (perhaps Achaean Greeks).

However, under Tudhaliya III (r. 1380–1360 B.C.) and his son Shuppiluliuma I (r. 1370–1330 B.C.), the situation was reversed. Shuppiluliuma consolidated the empire in the north and Hattusha was reconquered and strongly fortified. He then advanced into Syria, establishing Carchemish as a royal center. Egypt now seems to have recognized the Hittites as an equal power: indeed, a later Hittite text refers to an Egyptian queen (perhaps the widow of Tutankhamun) writing to Shuppiluliuma to request marriage with one of his sons. Plague, brought back to Anatolia from the Levant by Hittite soldiers and prisoners of war, cut short the achievements of Shuppiluliuma. However, his conquests were consolidated and expanded by his son Murshili II (r. 1330–1295 B.C.), whose greatest success was against Arzawa in the west, which was reduced to the status of a subject-state.

Under Muwatalli (r. 1295–1282 B.C.), the Hittite capital moved south to Tarhuntasha, perhaps because of the continued threat from the Gashga people. However, control of western Anatolia was maintained and possibly expanded with a treaty agreed between the Hittites and a certain Alaksandu of Wilusa (perhaps Troy). In the Levant, Hittite power was also strengthened when Egypt under Ramesses II attempted to expand beyond the region of Kadesh (Qadesh). Muwatalli's defeat of an Egyptian army led to Hittite control as far south as Damascus. Peace between Egypt and the Hittites was eventually established under Hattushili III (r. 1275–1245 B.C.), prompted perhaps by the growing power of Assyria in northern Mesopotamia.

Under Tudhaliya IV (r. 1245–1215 B.C.), Hattusha was further strengthened and the king completed the construction of a nearby religious sanctuary, known today as Yazilikaya (Turkish: "inscribed rock"). However, during his reign, the empire began to suffer setbacks. The Assyrians launched attacks against the eastern borders of the empire as well as in Syria, reducing Hittite territory in these regions. At the same time, Hittite dependencies in the west were being lost. Sometime around 1200 B.C., Hattusha was violently destroyed and never recovered. Who destroyed the capital is unknown but it was apparently part of the wider collapse of Hittite power. The reasons for the rapid disappearance of the Hittites, who had dominated Anatolia for centuries, remains unexplained. However, Hittite traditions were maintained in northern Syria by a number of dynasties established under the empire, such as at Carchemish, which continued to flourish through the early centuries of the first millennium B.C.