From the late 2nd century, the Roman Senate included several notable Syrians, including Claudius Pompeianus and Avidius Cassius.

Syria was of crucial strategic importance during the Crisis of the Third Century. In 244 AD, Rome was ruled by a native Syrian from Philippopolis (modern day Shahba) in the province of Arabia Petraea. The emperor was Marcus Iulius Philippus, more commonly known as Philip the Arab. Philip became the 33rd emperor of Rome upon its millennial celebration.

Roman Syria was invaded in 252/253 (the date is disputed) after a Roman field army was destroyed in the Battle of Barbalissos by the King of Persia Shapur I which left the Euphrates river unguarded and the region was pillaged by the Persians. In 259/260 a similar event happened when Shapur I again defeated a Roman field army and captured the Roman emperor, Valerian, alive at the Battle of Edessa. Again Roman Syria suffered as cities were captured, sacked and pillaged.

From 268 to 273, Syria was part of the breakaway Palmyrene Empire.

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