How Did the Seleucid Empire Collapse?
For most of the third and second centuries BC, the Seleucid Empire was the greatest of Alexander the Great’s Hellenistic successor states. Stretching from boundary of Persia to the Mediterranean Sea, and at times including parts of Anatolia, the Seleucid Empire was the largest of all the successor states, but it was also among the most culturally and politically important as well. The Seleucid Dynasty was headquartered in the newly built city of Seleucia and was in many ways the inheritor of ancient Mesopotamian culture as well as the torch bearer of Greek culture in the east, bringing the ideas of Hellenism to Mesopotamia but also allowing the natives to practice their ancient religion. Eventually, though, the greatness that was the Seleucid Empire came to a quick and violent end.
The Hellenistic world was a violent world and so by the mid-second century BC the enemies of Seleucids were many and on all sides. The Ptolemies, Pergamon, various other Macedonian rulers, and the Romans all threatened the Seleucids from the west, while the Parthians and their expansion was a problem in the east. The early Seleucid rulers probably could have effectively handled the plethora of enemies, but internal problems marked by a succession of weak rulers after Antiochus IV (reigned 175-164 BC) led to civil war. By the first century BC, the Seleucid state was a shadow of its former self and it took little effort by the Romans and Parthians to partition what was left of it among themselves.
The Seleucid Dynasty and empire was born when Seleucus I, who was one of Alexander the Great’s trusted generals, or Diadochi, was crowned king in 305 BC. In addition to being given control of Mesopotamia, Phoenicia, and Coele Syria (the inland region of the Levant), he was proclaimed “Nicator” (conqueror) by the other generals. Seleucus won his kingdom through military campaigning, expanded its border east into Persia and central Asia, and defended it from the other Diadochi, most notably Antigonus in 301 BC.  The conquering king then established his new kingdom as a beacon of Hellenistic culture by constructing Seleucia on the Tigris River near Babylon and dividing the empire into seventy-two provinces.  Seleucus I created a strong, viable Hellenistic kingdom and left his successors in a position to succeed.
Seleucus I’s successors engaged Ptolemaic Egypt in six wars for control of Syria, known as the Syrian Wars, from 274 to 168 BC. The wars ebbed and flowed, with Seleucus II (ruled 246-225 BC) losing Syria, and even Babylon temporarily to the Ptolemies, before Antiochus III (reigned 223-187 BC) was able to win back most of that territory for the Seleucids.  Antiochus III’s rule was the high water mark of Seleucid power: the Seleucids possessed the largest and most powerful Hellenistic kingdom and it was culturally on par with Egypt and Pergamon. But for every powerful kingdom in world history, there are several more waiting to take their place.
Parthia and Rome
Until the reign of Antiochus III, the Seleucids claimed most of Persia as theirs, but that began to change during Seleucus II’s rule. A new Persian ethnic group known as the Parthians, led by Arsaces I (ca. 247-217 BC) swooped down from the north to challenge the Seleucid claim to the land. Although not directly linked to the Achaemenid Persians, the Parthians viewed themselves as the true inheritors of Persia and the Seleucids as interlopers, so they immediately began challenging the Seleucid claim to the region.  Seleucus II was able to temporarily beat back the Parthians,  but the challenge to Seleucid hegemony in the east had been established and things would only get more difficult there for later Seleucid kings.
As much of a threat the Parthians posed in the east, the situation was even worse and far more complicated in the west. In addition to the nearly constant wars with Ptolemaic Egypt and the other Greek-Macedonian kingdoms, the Seleucids had to contend with the rising ambitions of Rome. When Antiochus III invaded mainland Greece in 193 BC, the Romans initially stayed on the sidelines, but when they saw an opening they joined an alliance with the Hellenistic Kingdom of Pergamon against the Seleucids. The forces then met at the Battle of Magnesia in Anatolia in December 190 or January 189.  Strabo wrote how the Romans and Pergamon won and took land at the Seleucids’ expense.
“Eumenes fought on the side of the Romans against Antiochus the Great and against Perseus, and he received from the Romans all the country this side the Taurus that had been subject to Antiochus.” 
Seleucid Dynastic Succession Problems
As intense as the external pressure being exerted on the Seleucid Empire was, the biggest problems came from within. A series of weak rulers, succession problems, and ultimately civil war made the Seleucid Empire ripe to be dismantled by the Parthians and Romans. It is difficult to say precisely when the Seleucid Dynasty’s internal health began declining, but it became apparent after the crown passed from Antiochus IV to his son, Antiochus V (reigned 164-161 BC). It was immediately clear to most that Antiochus V, who was only nine when he became king, was unfit to rule and was especially weak in the face of growing Roman power. It was at that point when Demetrius, the son of former King Seleucus IV (reigned 187-175 BC), decided to leave Rome, where he was being held as a hostage, in order to claim the Seleucid throne.  The third century AD Roman historian, Cassius Dio, wrote:
“Now Demetrius, the son of Seleucus, and grandson of Antiochus, who was staying in Rome as a hostage at the time of his father’s death and had been deprived of the kingdom by his uncle Antiochus, had asked for the domain of his father when he learned of the death of Antiochus, but the Romans would neither help him to get it nor permit him to depart from Rome; and he, in spite of his dissatisfaction, had remained quiet. But when this affair of Lysias occurred, he no longer delayed, but escaped by flight and sent a message to the senate from Lycia stating that it was not his cousin Antiochus, but Lysias that he was attacking, with the purpose of avenging Octavius. And hastening to Tripolis in Syria, he won over the town, representing that he had been sent out by the Romans to take charge of the kingdom; for no one had any idea of his flight. Then after conquering Apamea and gathering a body of troops he marched on Antioch; and when the boy and Lysias offered no opposition through fear of the Romans, but came to meet him as friends, he put them to death and recovered the kingdom.” 
The Seleucid throne went into a freefall after Demetrius became king. Although he ruled for more than ten years, he had set the precedent for violent usurpation that would mark the remainder of the Seleucid Dynasty’s history. A pretender to the throne named Alexander Ballas (ruled 150-145 BC) overthrew Demetrius, mainly due to the political connections he made. Although Demetrius claimed to have been a long lost son of Antiochus IV, his claim was dubious and it appears he derived most of his real power from the Ptolemies of Egypt. He married Ptolemy II’s daughter, Cleopatra Thea, which gave the Ptolemies indirect control of the Seleucid Empire. The tangled web of power did not end well for Alexander, though, as his former father in law Ptolemy VI turned against him. Alexander was defeated by a force led by Ptolemy VI and Demetrius II at the Battle of Antioch in 145, further sending the Seleucid Empire into more chaos. 
The Seleucid Dynasty was briefly stabilized under the rule of Antiochus VII (ruled 139-129 BC), but it was well on its way to its death knell at that point. Antiochus marched against the Parthians in 130 BC, taking back most of Mesopotamia and freeing Demetrius II who had been held in captivity, but he died in battle, leaving the throne open to more intrigue. 
After Antiochus VII died, the throne basically passed to Cleopatra Thea, who killed her husband of the moment, Demetrius II, in order to place their son, Antiochus VIII (ruled 125-96 BC), on the throne. By then the Seleucid Empire descended into full-scale civil war and was a shadow of its former self, being reduced in area to Syria.  The Parthians were in firm control of Mesopotamia by the beginning of the first century BC, but the final blow came when Rome claimed the Levant in 64 BC, thereby extinguishing the Seleucid royal line. 
The Seleucid Empire was the greatest of the Hellenistic empires in terms of size and one of the most influential in terms of politics and culture. The early Seleucid kings expanded their already large empire by force to the east and west, played a major role in the power politics of the other Hellenistic kingdoms, and exported Greek-Hellenistic culture throughout Mesopotamia and the Near East. But as the Seleucids built their empire from the late fourth through the early second centuries BC, Rome and Parthia began challenging their hegemony in Mesopotamia and the Levant. Eventually, though, internal dissention and succession problems within the Seleucid royal house proved to be the catalyst that allowed the Romans and Parthians to partition the Seleucid Empire and add its territory to their growing empires.
- Bryce, Trevor. Ancient Syria: A Three Thousand Year History. (Oxford: Oxford University Press, 2014), pgs. 164-66
- Price, Simon. “The History of the Hellenistic Period.” In The Oxford History of Greece and the Hellenistic World. Edited by John Boardman, Jasper Griffin, and Oswyn Murray. (Oxford: Oxford University Press, 2001), p 374
- Bryce, p. 187
- Brosius, Maria. The Persians: An Introduction. (London: Routledge, 2010), pgs. 84-85
- Strabo. Geography. Translated by Horace Leonard Jones. (Cambridge, Massachusetts: Harvard University Press, 2001), XI, 8, 8
- Bryce, p. 189
- Strabo, XIII, 4, 2
- Bryce, pgs. 207-8
- Cassius Dio. Roman History. Translated by Earnest Cary. (Cambridge, Massachusetts: Harvard University Press, 1954), XX, 9, 25
- Bryce, pgs. 209-20
- Bryce, pgs. 212-13
- Price, p. 367
- Bryce, p. 221