Adramyttium was founded by, and named after, Adramytos, the son of King Alyattes of Lydia. Prior to his ascension to the throne, Croesus, Alyattes ' successor, was governor of a district centered on Adramyttium. Following the fall of the Kingdom of Lydia in 546 B.C. Adramyttium came under the rule of the Persian Empire and was administered as part of the satrapy (province) of Hellespontine Phrygia from the early 5th century B.C. onward. In 422 BC, Pharnaces, the satrap of Hellespontine Phrygia, offered asylum to exiles from the island of Delos, who settled in the city. Thereafter Adramyttium was considered a Greek city. Arsaces, a general subordinate to Tissaphernes, the satrap of Lydia and Caria, massacred a number of the Delian exiles. The Delians returned to Delos in 421/420 BC when the Athenians permitted them to do so. Following the end of the Peloponnesian War in 404 B.C., Adramyttium came again under the control of Mytilene. The Ten Thousand, a Greek mercenary force, traveled through Adramyttium during their march along the coast. Mytilene retained control of Adramyttium until 386 B.C., after which the city formed again part of the Persian Empire by the terms of the Peace of Antalcidas. During the Great Satraps ' Revolt, Ariobarzanes, satrap of Hellespontine Phygia, joined the revolt against Artaxerxes II in 367 BC. Autophradates, satrap of Lydia, and Mausolus, satrap of Caria, besieged Ariobarzanes at Adramyttium in 366 B.C. However, the siege of Adramyttium was abandoned following the arrival of Agesilaus II, King of Sparta, in 365 B.C.

Following his victory at the Battle of the Granicus in 334 BC, Adramyttium came under the control of Alexander the Great. After Alexander 's death in 323 BC, his empire was divided among the Diadochi at the Partition of Babylon, and Leonnatus was appointed satrap of Hellespontine Phrygia. At the Partition of Triparadisus in 321 B.C., Arrhidaeus succeeded Leonnatus as satrap of Hellespontine Phrygia. In 319 BC, Adramyttium and Hellespontine Phrygia were seized by Antigonus I Monophthalmus, satrap of Greater Phrygia. Adramyttium and Hellespontine Phrygia remained under the control of Antigonus until the Fourth War of the Diadochi; the city was taken by force by Prepelaus, a general of Lysimachus, Basileus of Thrace, in 302 BC. Adramyttium and Lysimachus ' other Anatolian territories were annexed to the Seleucid Empire after Lysimachus ' defeat at the Battle of Corupedium in 281 B.C. An artificial port was constructed at Adramyttium in the early third century BC, which subsequently allowed the city to overshadow the neighboring port of Cisthene.

Adramyttium came under the control of the Attalid dynasty of Pergamon during the rule of Eumenes I, a nominal vassal of the Seleucid Empire, in the mid-third century B.C. The alliance between Attalus I, Eumenes 's successor, and Rhodes during the Cretan War led Philip V, King of Macedonia, to invade the Kingdom of Pergamon and pillage the countryside surrounding Adramyttium in 201 BC. As an ally of Rome, Pergamon fought in the Roman–Seleucid War against the Seleucid Empire. In 190 B.C., Antiochus III plundered the countryside surrounding Adramyttium, but the appearance of a Roman–Pergamene fleet prevented him from taking the city. In the second century B.C., cistophori, the coinage of the Kingdom of Pergamon, were minted at Adramyttium. Attalus III, the last King of Pergamon, bestowed his kingdom to the Romans in his will in 133 B.C.

Manius Aquillius, governor of the province of Asia from 129 to 126 B.C., rebuilt the road that connected Adramyttium and Smyrna. During the First Mithridatic War, the strategos Diodorus had the the city council killed and gave control to Mithridates VI, King of Pontus. In 88 B.C., Mithridates ordered the execution of all Roman settlers. At Adramyttium, the Romans were driven into the sea and slaughtered. At the end of the war, Xenocles of Adramyttium, was sent to Rome to defend the actions of the city.Adramyttium, was deprived of its autonomy, and was henceforth obligated to pay regular taxes to Rome. According to the Acts of the Apostles, whilst en route to Rome, St. Paul departed Caesarea Maritima on a ship from the city of Adramyttium which took him to Myra in Lycia.

Adramyttium may have moved the 13 kilometers northeast to its current location when Trajan rebuilt the city after an earthquake. Another possibility is that Adramytium was relocated inland after it was destroyed by Genoese pirates in 1197.