The Seleucid kingdom dated its beginning from 312 BC when Seleucus I Nicator seized Babylon in his own name; but his empire was not really established until Antigonus I was defeated at Ipsus in 301 BC, and Asia Minor was not included until Lysimachus was eliminated in Lydia in 281 BC.

When Seleucus I was assassinated the next year, his son by his Persian wife Apame had already married his step-mother Stratonice and was co-ruling from Seleucia on the Tigris; Antiochus I became the second Seleucid king, ruling over the Asian empire Alexander had taken from the Persians with the exception of Egypt, Cyrene, and those parts of southern Syria which Ptolemy held temporarily and which the Seleucids and Ptolemies fought over until the end of the third century BC.

This Seleucid empire extended from the Aegean Sea to what is now Afghanistan containing about one and a half million square miles and about thirty million people compared to seven million in Egypt and four million in Macedonia. However, it was not long before this cumbersome empire governed by Macedonian soldiers lost vast territories. Antiochus defeated the Galatians in Anatolia in 275 BC and invaded lower Syria the next year.

A more western capital was built for the king called Antioch on the Orontes in Syria, taking over the Macedonian population of nearby Antigonia, while the crown prince continued to govern in Seleucia on the Tigris, where most of the Babylonian population moved. Another Seleucia called Pieria was established on the Phoenician coast; but this was lost to the Ptolemies 241-219 BC until the Seleucids built a strong navy. Various heavy taxes were levied to support the empire and its military garrisons, whose soldiers were given farms and organized into cities with Hellenic assemblies, judges, and laws. Many Hellenistic cities were established with the designated number of 5,300 male citizens, close to what was recommended in Plato's Laws, making a city of about 25,000 Greek inhabitants plus slaves. Trade was facilitated by a single currency, and silk came all the way from China.

Antiochus I Soter (r. 280-261 BC) was credited with driving out the Gauls and tried to take Syria from the Ptolemies with military force but was turned away. In the reign of Antiochus II Theos (r. 261-246 BC), who was admired for killing the Milesian tyrant Timarchus, Persia broke away. By the time he was poisoned by his first wife Laodice, the Greeks in prosperous Bactria led by Diodotus had become independent, followed by Hyrcania and Parthia led by the brothers Arsaces and Tiridates. Arsaces was killed in battle, but Tiridates ruled Parthia for 37 years and moved the capital to Hellenized Hecatompylos.

Ptolemy II was forced to cede Ionia, Cilicia, and Aegean islands to Antiochus II in 255 BC. Three years later Antiochus II repudiated his wife Laodice and married Ptolemy's daughter Berenice. Seleucus II (r. 246-226 BC) tried to recover the east with his army, but had to return to Antioch to quell a revolt. Seleucus II appointed his brother Antiochus the Hawk regent in Asia Minor, and they fought each other for a decade while the empire shrank.

After both Antiochus the Hawk in Thrace and his brother Seleucus II were murdered the same year, Seleucus III tried to reconquer Asia Minor but was defeated by Pergamum's Attalus I and was then assassinated by his own men in 223 BC; he was succeeded by his brother, 18-year-old Antiochus III (called "the Great"), who appointed Achaeus to direct the war in Asia Minor. Two brothers, Molon and Alexander, satraps in Babylon and Persis respectively, declared themselves independent kings and were followed by Media king Atropatene, who threw off his vassalage.

Antiochus III marched his imperial army east, and by 219 BC abandoned by their armies, Molon and Alexander committed suicide. Achaeus, whose father was a hostage in the court of Ptolemy III, broke off the siege of Pergamum and heading toward Antioch, declared himself king; but his troops failed to go along. Antiochus III took advantage of a dynastic succession in Egypt to attack Palestine; but after regaining Seleucia Pieria he was eventually defeated at Raphia in 217 BC.

Three years later Antiochus III besieged Achaeus at Sardis and, after he was betrayed, had his body mutilated. Having ended the civil war and regained some of western Anatolia, the energetic Antiochus III next marched east through Armenia and Media to take on the Parthians. To finance this adventure Antiochus III took the treasury from the temple of the goddess Anahita near Ecbatana. The Seleucid army captured Hecatompylos, causing Parthian king Artabanus I to withdraw into Hyrcania; but Antiochus III could do no more than accept their promise of fealty and tribute. Then Antiochus III attacked independent Bactria, which would not yield. Euthydemus argued that their conflict would only help the Sacae nomads; so by conferring a gift of elephants and supplies, Euthydemus was accepted as a vassal king, as his son Demetrius married a daughter of Antiochus III.

After eight years Antiochus III eventually returned to Seleucia on the Tigris, having gone through Afghanistan to India and back through Arachosia and Seistan; but these regions were too spread out to be governed by his empire. Another dynastic succession in Egypt stimulated Antiochus III to negotiate with Macedonian Philip V to divide up Egypt's Asian possessions. The Seleucid army then defeated the Egyptians at Panium in 200 BC, and five years later Ptolemy V surrendered his Asian holdings in a treaty and accepted Antiochus' daughter Cleopatra I as a bride. By then the ambitious Antiochus III had already crossed over into Europe to take Lysimachia in Thrace. He sent ambassadors to Rome asking for friendship; but the Roman senate replied that they would be friends if Antiochus left the Greeks in Asia free and independent and if he kept away from Europe. Antiochus would not release the Aeolians and Ionians who were accustomed to obeying Asian kings. Antiochus III with 10,000 men sailed across the Aegean and took Euboea, Thebes, and Thessaly, where he alienated Philip V. Smyrna and Lampsacus appealed to Rome, which gained the support of Philip V's Macedonians, and the Seleucids were defeated at Thermopylae, Antiochus III barely escaping by ship to Ephesus.

Withdrawing from Thrace and granting autonomy to Smyrna and Lampsacus were now not enough for Rome, which demanded that the Seleucids clear out of Anatolia. Eumenes II of Pergamum helped the Roman soldiers at Magnesia defeat the more numerous forces of Antiochus III, who sued for peace. Publius Scipio replied that the grasping nature of Antiochus caused his misfortunes; he should not have invaded Europe and taken away the liberty of the people Romans had freed. In the treaty of Apamea in 188 BC Scipio imposed the same conditions, demanded twenty hostages including his son Antiochus, a reduction of ships to twelve, and payment to Rome for the cost of the war totaling 15,000 talents over the next twelve years. The over-reaching ambition of Antiochus III had broken the Seleucid power.

Parthian king Phriapatius reconquered the regions south of the Caspian Sea, and the Media Atropatene declared independence. Seleucus IV (r. 187-175 BC) was assassinated by a conspiracy of court officers; but his brother Antiochus IV Epiphanes (r. 175-163 BC), who had been a hostage in Rome, modernized the Seleucid army along Roman lines, and in 169 BC he sent troops east to Bactria and then attacked Memphis in Egypt. However, he had to withdraw before Roman power in Egypt, and his taking of the treasury from the temple at Jerusalem and his Hellenistic religious reforms brought on a Judean revolt. Shortly after the death of Antiochus IV, Judea and Commagene in Syria both became independent kingdoms during the reign of Demetrius I until he was killed and succeeded by Balas in Syria. The Seleucids lost Mesopotamia to the Parthians, whose king Mithridates I (c. 171-138 BC) captured Seleucid king Demetrius II in 140 BC.

An invasion by Antiochus VII to recover Media and Babylon eventually ended in his defeat and death in 129 BC. Starting in 150 BC two rival branches of the Seleucid dynasty fought each other for the Syrian kingdom that remained until the Romans took it over in 64 BC. In Bactria Demetrius moved east into Taxila and in 175 BC sent his general Menander to conquer much of the northern Mauryan empire including the capital at Pataliputra. Eucratides I (c. 171-155 BC) was succeeded by Menander (c. 155-130 BC), and after his queen Agathocleia's regency, Strato I ruled for half a century while Amyntas, a descendant of Eucratides I, reconquered some territories from the Scythians; but by the middle of the first century BC there were no more Greeks ruling in this area. Bithynia and Caspian regions east of it never were conquered by Alexander nor by his successors and remained independent kingdoms. Nicomedes I (r. 279-250 BC), the son of Bithynian king Zipoetes I (r. 297-279 BC), encouraged Hellenistic culture but also asked for the aid of the Gauls against Antiochus I which led to the establishment of these Celts in Galatia. Bithynia thrived under Prusias I (c. 230-182 BC) and allied itself with Rome; but Nicomedes IV at his death in 74 BC bequeathed the kingdom to Rome. In Pontus Mithridates I ruled 301-266 BC, while at Comana the priests of the earth-mother goddess Ma dominated 6,000 male and female slaves.

In 183 BC Pharnaces I, who according to Polybius surpassed all previous kings in his contempt for the laws, attacked Sinope, then took Tium in Bithynia and invaded Galatia. After three Roman embassies and pressure from Rhodes three years later Pharnaces made peace "for all time" with Eumenes II of Pergamum and Ariarathes of Cappadocia, renouncing Galatia, restoring Tium and prisoners of war while paying 1200 talents. Cappadocia governed itself as a vassal of the Seleucids, and Ariarathes III was named king there in 255 BC. With Greek administrators Pontus grew in power until Mithridates V (c. 150-120 BC) was the most powerful king in Asia Minor. His son Mithridates VI called Dionysius (c. 120-63 BC) tried to expand the kingdom and fought numerous wars with the Romans until Pontus was finally absorbed into the Roman province of Bithynia by Pompey, though Tigranes I, who had conquered Syria in 83 BC, was able to hang on to Armenia until his death in 56 BC. Mithridates II reigned in Parthia from 123 to 86 BC. Philetaerus was military governor of Pergamum under Antigonus I, then for Lysimachus, before contributing the enormous treasure to the Seleucids and ruling there for them. However, his son Eumenes I (r. 263-241 BC) with the help of Ptolemy III became independent. Pergamum's Attalus I Soter (r. 241-197 BC) defeated the Galatians and sided with the Romans and the Aetolians against Macedonia's Philip V. His son Eumenes II (r. 197-160 BC) expanded Pergamum to half of Asia Minor including Lydia and Phrygia. Pergamum was Hellenized with military settlements and a library that rivaled Alexandria's; but Attalus III (r. 138-133 BC) bequeathed his royal estates and treasures to Rome, which took the kingdom, squelched a revolt, and made it the province of Asia.