Damascus was conquered by Alexander the Great. After the death of Alexander in 323 BC, Damascus became the site of a struggle between the Seleucid and Ptolemaic empires. The control of the city passed frequently from one empire to the other. Seleucus I Nicator, one of Alexander's generals, made Antioch the capital of his vast empire, which led to the decline of Damascus' importance compared with new Seleucid cities such as Latakia in the north. Later, Demetrius III Philopator rebuilt the city according to the Greek hippodamian system and renamed it "Demetrias".
In 64 BC, the Roman general Pompey annexed the western part of Syria. The Romans occupied Damascus and subsequently incorporated it into the league of ten cities known as the Decapolis because it was considered such an important center of Greco-Roman culture. According to the New Testament, Saint Paul was on the road to Damascus when he received a vision of Jesus, and as a result accepted him as the Messiah. In the year 37, Roman Emperor Caligula transferred Damascus to Nabataean control by decree. The Nabataean king Aretas IV Philopatris ruled Damascus from his capital Petra. However, around the year 106, Nabataea was conquered by the Romans, and Damascus returned to Roman control.
Damascus became a metropolis by the beginning of the 2nd century and in 222 it was upgraded to a colonia by the Emperor Septimius Severus. During the Pax Romana, Damascus and the Roman province of Syria in general began to prosper. Damascus's importance as a caravan city was evident with the trade routes from southern Arabia, Palmyra, Petra, and the silk routes from China all converging on it. The city satisfied the Roman demands for eastern luxuries.
Little remains of the architecture of the Romans, but the town planning of the old city did have a lasting effect. The Roman architects brought together the Greek and Aramaean foundations of the city and fused them into a new layout measuring approximately 1,500 metres (4,900 ft) by 750 metres (2,460 ft), surrounded by a city wall. The city wall contained seven gates, but only the eastern gate (Bab Sharqi) remains from the Roman period. Roman Damascus lies mostly at depths of up to five meters (16.4 ft) below the modern city.
The old borough of Bab Tuma was developed at the end of the Roman/Byzantine era by the local Eastern Orthodox community. According to the Acts of the Apostles, Saint Paul and Saint Thomas both lived in that neighborhood. Roman Catholic historians also consider Bab Tuma to be the birthplace of several Popes such as John V and Gregory III.