After Alexander the Great died (323 B.C.), the fate of Ionia and Chios devolved successively to the power of the Macedonian King Antigonos, the One-Eyed, the Macedonian general Lysimachus, and the kings of Ptolemaist and Pergamum. After the dissolution of the Corinthian alliance Chios did not participate in any coalition, therefore, when Antigonos defeated the Macedonian general Kleito, Chios was under his command in a way and became member of the Ionian Public. After the death of eighty-year-old Antigonos in the battle of Ipsou (301 B.C.) Chios would devolve to Lysimachus, as well as other cities of the Minor Asia. Chios was under the power of Lysimachus until the battle of Kouropedio of Lydia in 281 B.C., where Lysimahos was defeated and killed.

From 276 B.C. Chios devolved to the kingdom of Ptolemaist of Egypt. We can see a characteristic testimony on an inscription on a slab that reports "in favor of King Ptolemaist and Queen Arsine". From the means of third century B.C. Chios appears to gain its autonomy and to establish diplomatic relations with the Etoloi who defeated the Galatians in Delphi and occupied the Pan-Hellenic temple of Delphi, which they controlled until the moment they were conquered by the Romans in 179 B.C. The Etoloi established the Games as a memorandum of their victory. They were called “Sotiria” (Salvation), and after their suggestion they were recognized as Panhellenic Games. Chios not only accepted their demand for the recognition of the Games, but it also congratulated them on their bravery against the barbarians (Galatians). The next step for Chios was to contracting alliance with them so as its ships could sail without the fear of being attacked by robbers and pirates.

Many Chians who had been exiled became pirates and raided on the coasts of Chios, as well as on the entire area of Ionia. During that period there were the towers, a main proof for the fear the pirates caused, built in several areas for the protection of the inhabitants from them. During the period 241 – 197 B.C. Pergamum, ruled by King Attalos turned out to be a great power in the Minor Asia. King Attalos in order to show his friendship to the Greeks allocated a great amount of money to them. Chios was one of the cities which benefited a lot from the money the King donated.

In the Hellenistic years Chios did not have any remarkable poets to show off. On the other hand, three philosophers, the academic Apelles, Theodore and Ariston the Siren (who opened in Kynosarges of Athens his own School and elected a lot of students who were called Aristonioi) were very well known. Simonaktidis from Chios was famous for his cooking; he was known as one out of the seven best chefs of the third B.C. century. He owned his good reputation to the way he cooked of conger (a kind of fish). There were also some great sculptors, such as Lycia, Periandros’s son, Menippos and his son Zinodotos. The geographer Skymnos and the agronomist Agathocles, whose book about agriculture was also used by Roman writers, were also very famous Chians.