Alexander the Great conquered Syria along with the rest of the known world before his death in 323 BC. On his death his generals attempted to enforce claims to his empire; some tried to take it all and failed; others, like Ptolemy, limited their ambitions and succeeded. One of Alexanders generals, Seleukos, set himself up in the eastern provinces; he had wanted it all, but was unable to have his way, so he settled for what he could get.

Seleukos defeated those who attempted to recover his territories; decisively beating Antigonos One-eye in 309/8 somewhere in the eastern satrapies; he then beat him again at Ipsos in 301, then defeated and captured Demetrios the Beseigerin 285, then crushed Lysimachos at Corupedion in 281 BC, before being assassinated by a protg . His successors briefly held a vast eastern empire, before it began to crumble.

Seleukoss son Antiochos I (280-261 BC) ruled with a strong hand, among other things crushing the Gaulish invaders and penned them up in Galatia where they could be recruited as mercenaries; but his son Antiochos II Theos (i. e., the God) was addicted to other activities than warfare. His enemies were quick to take advantage. Both Baktria and Parthia broke away during this reign. His sons Seleukos II Kallinikos and Antiochos Hierax (the Hawk) fought for control, and although Seleukos won his kingdom on his death was rather less than it had been.

The long reign of Antiochos III the Great brought about a revival of Seleukid power, at least for a while: he reestablished his authority in the breakaway provinces. He found, however, that he could make little headway against Egypt; and the intervention of Rome after the defeat of the Macedonians at Cynoscephalae in 197 brought Antiochos into conflict with a power of quite another order. He committed his blunder at the request of the Aetolians, who wanted more than the Romans were willing to provide, and got beaten at Thermopylae and Magnesia-ad-Sipylum. In the latter battle Antiochos led a successful cavalry charge, like Demetrios the Besieger, among others; like them he pursued too far while his infantry got crushed. He ended up having to pay a huge indemnity to the Romans, and in the course of looting a temple to help raise cash he was assassinated.

His son Seleukos (187-175 BC) was competent enough; but hen he fell to an assassin his brother Antiochos IV Epiphanes (Divine Manifestation; parodied as Epimanes, Lunatic, 175-164 BC), the most famous, or infamous, of the Seleukids attempted to regain lost ground. What he did accomplish was to stir the Jews into rebellion due to his interference in their affairs; this plus his attempts to stabilize his frontiers, which caused the Romans to look at him with suspicion, and lost him more territory. His son, Antiochos V, succeeded as a minor, but not for long. His uncle Demetrius, set aside by Epiphanes, recovered his throne in 162, only to lose it to a pretender, Alexander I Balas, in 150. From then on the Seleukid kingdom was a prize to be fought for by a succession of usurpers, most of whom were dissolute and incompetent.

The only one among the successors of Demetrios who was neither dissolute nor incompetent was Antiochos VII Sidetes (viz., from Side where he was raised; 138-129 BC), who among other things brought the Jewish state back under Seleukid rule for a few years, but was killed in battle against the Parthians. From then on the Seleukid state declined rapidly; it provided employment for such characters as the Egyptian who was set up with Ptolemaic backing as a son of Alexander Balas; the second Alexander, called Zabinas (i.e., Purchased), he was at least a decent character, unlike his rival Demetrius II Nikator. He had been installed by the Ptolemies for their purposes, and when he showed signs of independence they got rid of him in favor of Alexander VIII Gryphos (Hook-nose; 125-96 BC), who was firmly under the control of his mother Cleopatra, daughter of Ptolemy VI until she tried to poison him; he got her to drink it instead. He did nothing worthy of note for the rest of his rather long and certainly inglorious reign, for most of which he had to fight a pretender, his half-brother Antiochos IX Kyzikenos.

The Seleukids sank so rapidly thereafter that by 83 the Syrians called in a foreigner, Tigranes of Armenia, to get rid of all the squabbling candidates. Tigranes cleaned them all out, and reigned until 69, when the Romans defeated him. The Romans set up a puppet, Antiochos XIII Asiatikos, as a pliable client; he was in turn murdered by the Arab sheik Sampsigeramos in 64. Syria passed definitively into Roman hands; the only remnant of the Seleukids being a series of tetradrachms issued in the name of Philip Philadelphos, but dated by a local era from 64/3 BC, as late as the 30s.