After the death of Alexander III of Macedon in 323 B.C., the territories he had conquered were divided between his generals, the so-called Diadochi. Alexander’s friend Seleucus Nicator (r. 312–281 B.C.) became king of the eastern provinces—approximately modern Afghanistan, Iran, Iraq, Syria, and Lebanon, together with parts of Turkey, Armenia, Turkmenistan, Uzbekistan, and Tajikistan. The huge kingdom had two capitals, which Seleucus founded in around 300 B.C.: Antioch in Syria and Seleucia in Mesopotamia (Iraq). Seleucus established a dynasty that lasted for two centuries, during which time Hellenistic art, a fusion of Greek and Near Eastern artistic traditions, developed and flourished.

Around 246 B.C., the Seleucids lost substantial territory in the east, as a nomadic group called the Parni settled in the satrapy (administrative district) of Parthia in northern Iran. In the same period, the satrapy of Bactria (Afghanistan) claimed independence. However, the Seleucid king Antiochus III “the Great” reconquered much of these regions between 209 and 204 B.C. when he campaigned in the east as far as India. In the west, the Seleucid king fought several wars with his fellow Macedonians, the Ptolemaic dynasty of Egypt. The Egyptian forces were crushed in 200 B.C., and the Ptolemies were forced to cede Palestine to Antiochus, who was proclaimed conqueror of the East.

In 196 B.C., Antiochus crossed the Hellespont and two years later had added the region of Thrace to his empire. This brought the Seleucid empire into direct contact with the dominant Mediterranean power of Rome. In 190 B.C., Roman soldiers for the first time set foot in Asia, and the following year a Seleucid army of 75,000 met Roman forces numbering only 30,000 at the Battle of Magnesia. Despite the odds, Antiochus was completely defeated, and the Seleucid empire lost its possessions in Anatolia (Turkey).

In 168 B.C., Antiochus IV desecrated the Temple in Jerusalem. In response, the Hasmonaean family organized a guerrilla army against the Seleucids. The leader of the Jewish forces, Judah, known as the Maccabee (“hammer”), captured the Temple, and eventually drove the Seleucids out of Palestine. In the same period, the Parni were establishing their power across Iran and Mesopotamia, forming the Parthian empire: Seleucia was captured in 141 B.C. By the first century B.C., Seleucid power was further undermined when King Tigranes of Armenia expanded his kingdom into Syria. This brought Roman forces back to Asia, and in 64 B.C. the Roman general Pompey arrived in Antioch, having established Syria as a Roman province and bringing to an end the remnants of the Seleucid kingdom.