Antioch on the Orontes (; Greek: Ἀντιόχεια ἡ ἐπὶ Ὀρόντου, Antiókheia hē epì Oróntou, Learned Koine Greek pronunciation: [anti.ó.kʰeː.a hɛː e.pí orón.tuː]) was a Hellenistic Greek city founded by Seleucus I Nicator in 300 BC. It was one of the greatest and most important Greek cities of the Hellenistic period. The city served as the capital of the Seleucid Empire and later as regional capital to both the Roman and Byzantine Empire. During the Crusades, Antioch served as the capital of the Principality of Antioch, one of four Crusader states that were founded in the Levant. Its inhabitants were known as Antiochenes. The modern city of Antakya, in Hatay Province of Turkey, was named after the ancient city, which lies in ruins on the Orontes River and did not overlap in habitation with the modern city.

Antioch was founded near the end of the fourth century BC by Seleucus I Nicator, one of Alexander the Great's generals, as one of the four cities of the Seleucis of Syria. The city's location offered geographical, military, and economic benefits to its occupants; Antioch was heavily involved in the spice trade and lay within easy reach of the Silk Road and the Royal Road. Seleucus encouraged Greeks from all over the Mediterranean to settle in the city. During the late Hellenistic period and Middle Roman Empire, Antioch's population may have reached a peak of over 500,000 inhabitants (most generally estimate between 200,000 and 250,000), making the city the third largest in the Empire after Rome and Alexandria and one of the most important cities in the eastern Mediterranean. The city was the capital of the Seleucid Empire from 240 BC until 63 BC, when the Romans took control, making it capital of the province of Syria and later of Coele Syria. From the early fourth century, Antioch was the seat of the Count of the Orient, head of the Diocese of the East. The Romans provided the city with walls that covered almost 450 hectares (1,100 acres), of which one quarter was mountain, leaving 300 ha (750 acres) – about one-fifth the area of Rome within the Aurelian Walls.

The city was also the main center of Hellenistic Judaism at the end of the Second Temple period. Antioch was part of the pentarchy and was called "the cradle of Christianity" as a result of its longevity and the pivotal role that it played in the emergence of early Christianity. The Christian New Testament asserts that the name "Christian" first emerged in Antioch. The city declined to relative insignificance during the Middle Ages due to warfare, repeated earthquakes, and a change in trade routes. The city still lends its name to Greek Orthodox Patriarchate of Antioch, one of the most important churches of the Levant and eastern Mediterranean.

The city is sacred for Muslims who visit the Habib-i Najjar Mosque, the site containing the tomb of Habib the Carpenter, mentioned in Surah Yā-Sīn of the Koran.