The Roman commander Pompey conquered the city in 64 BC and made it the capital of the Roman province of Syria; a status it retained throughout the remainder of the Roman period till the invasion of Arabs in 637/38.

Under the Roman Rule, Antioch became one of the most beautiful cities of the empire. As an elegant and cosmopolitan city famous for its sophistication, for the grand style of its buildings and broad avenues, its quality of life and cultural diversity, Antioch ranked with Rome, Alexandria and Constantinople as one of the four great cities of the Roman world. Its residents enjoyed grand public baths, spectacles and theatrical performances.

The city's location along the major trade route linking East and West contributed vastly to its prosperity. Most important, the siting of the city on a navigable river about fifteen and a half miles (a day's sail) from its Mediterranean port at Seleucia Pieria, afforded great economic and starategic advantages. Camel caravans carrying goods from the East stopped at Antioch to do business with sea traders from the Mediterranean. The fertility of the Amik plain and the lower Orantes valley produced favorable climatic conditions for agriculture, and the city was well supplied with grain, fresh produce, oil and wine. Fed by springs, Antioch's abundant waters were a source of pride and pleasure for its inhabitants. At its height in the 4 th century AD, the city covered three square miles with a population of 300 000 citizens and freedmen, not including slaves and children. Several religious faiths and ethnic groups, Greeks, Jews, Syrians, Christians and Romans converged to create a splendid cosmopolitan character.

Julius Caesar visited the city in about 47 BC. The most important public building constructed at the time was the basilica which he called after his own name, the Kaisarion, the oldest basilica in the east, followed by a public bath, an aqueduct and an amphitheater. Augustus and subsequent emperors continued building projects. Baths, theaters and residential districts were constructed on the Roman model as well as several temples to Roman deities.There were at least four gates that led into the city along its major avenues. One of these avenues was a grand colonnaded street that crossed Antioch from the north at the Aleppo Gate to the south at the Daphne Gate and covered a distance of nearly two miles and more than 10 meters wide. This was the first and grandest of such monumental avenues in the Roman world. Along each side of the roadway was a covered portico for pedestrians and at intervals all along the length of the street stood bronzes and statues. Excavations in the 1930s revealed that this famous colonnaded avenue of Roman Antioch lay beneath Kurtulus Caddesi, the main avenue of modern Antakya today. It is thought that the avenue was constructed by Herod the Great around 30 BC.

According to textual sources, the island in the Orantes River, now covered over by deposits, was the site of the palatial complex established during the Seleucid era. In the reign of Emperor Diocletian (284 - 305 AD), the imperial residence was rebuilt along with several baths and Hippodrome where chariot races took place once a week. The imperial palace was designed for the use of the emperor and his court when he visited Antioch. Also on the island (but also not found) was the octagonal Great Church begun by Constantine the Great and completed by his son Constantius II. Several bridges spanned the river and connected the city with the island. The river was easily navigable by ships that carried cargo to and from the Mediterranean sea.

One of the major events in the history of Antioch was the foundation of the local Olympic Games.In 43, Claudius granted a petition of Antiochene notables to begin Olympic Games in their city, to be held every five years. These games became one of the most celebrated festivals of the Roman world and were second only to the games held at Olymipia (Greece). So important were these games that occasionally an emperor who grew angry with the citizens of Antioch put a halt to them, but they were always restored. The Stadium in Daphne was the site where most of the athletic events took place.

Antioch had a famous school of rhetoric, led in the fourth century by Libanios, teacher of Roman emperors and Christian bishops, whose writings captured the flavor of life in the city. "Who, seeing the city for the first time, would not think he had come to a festival?" wrote Libanios in the fourth century.His most distinguished students were St.John Chrysostom, patriarch of Constantinople, and the historian Ammianus Marcellinus (330 - 395) both of whom were also born here. Ammianus Marcellinus called the city as "the fair crown of the Orient".

Geography was key to the city's eminence, but also to its downfall. First, it was subject to frequent and devastating earthquakes. Secondly , the topography of the site made the city difficult to defend, and as the power of Rome began to wane Antioch became increasingly vulnerable to attack by invaders from the south and east.

The earliest recorded earthquake was in 148 BC when the city was so ruined that it went into a temporary decline. It was badly damaged again by tremors in 37 and 115 AD, with the emperor Trajan being nearly killed on the latter occasion. In 458 AD a major earthquake destroyed nearly all buildings on the island. Another major earthquake in 526 destroyed almost entire city and left 250 000 dead. Reconstruction had hardly begun when another quake hit in 528, ruining whatever had ben left standing, as well as the repairs that had begun, and claming some five thousand victims. City is renamed Theopolis (City of God) in an effort to secure badly needed divine protection .

During the mid-third century AD, Antioch was twice captured and sacked by the Persians, and on the latter occasion in 260 it was almost totally destroyed by fire. The Persians captured and burned down the city again in 540. Bubonic plague began two years later. Although no figures are availble, there is no doubt that it decimated the urban population. In 577 AD , a severe earthquake destroyed the whole of Daphne, though the damage at Antioch itself was not serious.

Despite the major repairs and investments of the Byzantine emperor Justinian I, the city never fully recovered afterwards. The former glory was lost forever. In 638 the Byzantine army was annihilated at the battle of Yarmuk by the Arabs, who within a few months conquered all of Syria, including Antioch. After more than three centuries of Arab rule, Antioch was recaptured by the Byzantines in 969 AD and was made an important frontier. In 1084 AD it was taken by Seljuk Turks.
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