Rising to the throne at the age of eighteen in April/June 223 BC, his early campaigns against the Ptolemaic Kingdom were unsuccessful, but in the following years Antiochus gained several military victories and substantially expanded the empire's territory.

A militarily active ruler, Antiochus restored much of the territory of the Seleucid Empire, before suffering a serious setback, towards the end of his reign, in his war against the Roman Republic.

Declaring himself the "champion of Greek freedom against Roman domination", he waged a four-year war against Rome beginning in mainland Greece in the autumn of 192 BC[5][6] before being decisively defeated at the Battle of Magnesia.

Only in Asia Minor, where the king's cousin, Achaeus, represented the Seleucid cause, did its prestige recover, driving the Pergamene power back to its earlier limits.

[18] In 209 BC Antiochus invaded Parthia, occupied the capital Hecatompylos and pushed forward into Hyrcania, winning the Battle of Mount Labus.

[13][20] Antiochus next, following in the steps of Alexander, crossed into the Kabul valley, reaching the realm of Indian king Sophagasenus and returned west by way of Seistan and Kerman (206/5).

[13] According to Polybius: He crossed the Caucasus and descended into India, renewed his friendship with Sophagasenus, king of the Indians, and received more elephants, raising their number to a total of one hundred and fifty, and provisioned his army once more on the spot.

[22] In 205/204 BC the infant Ptolemy V Epiphanes succeeded to the Egyptian throne, and Antiochus is said (notably by Polybius) to have concluded a secret pact with Philip V of Macedon for the partition of the Ptolemaic possessions.

Once more Antiochus attacked the Ptolemaic province of Coele Syria and Phoenicia, and by 199 BC he seems to have had possession of it before the Aetolian leader Scopas recovered it for Ptolemy.

[13] Antiochus then moved to Asia Minor, by land and by sea, to secure the coast towns which belonged to the remnants of Ptolemaic overseas dominions and the independent Greek cities.

The Romans followed up their success by invading Anatolia, and the decisive victory of Scipio Asiaticus at Magnesia ad Sipylum (190 BC), following the defeat of Hannibal at sea off Side, delivered Asia Minor into their hands.

[13] By the Treaty of Apamea (188 BC) Antiochus abandoned all the country north and west of the Taurus Mountains, most of which the Roman Republic gave either to Rhodes or to the Attalid ruler Eumenes II, its allies (many Greek cities were left free).

The NRSV says "They [the Romans] also had defeated Antiochus the Great, king of Asia, who went to fight against them with one hundred twenty elephants and with cavalry and chariots and a very large army.

He was crushed by them; they took him alive and decreed that he and those who would reign after him should pay a heavy tribute and give hostages and surrender some of their best provinces, the countries of India, Media, and Lydia.