According to Classical Greek mythology, Lesbos was the patron god of the island. Macar was reputedly the first king whose many "daughters" bequeathed their names to some of the present larger towns. In Classical myth his "sister", Canace, was killed to have him made king. The place names with female origins are likely to be much earlier settlements named after local goddesses, who were replaced by gods. Homer refers to the island as "Macaros edos", the seat of Macar. Hittite records from the Late Bronze Age name the island Lazpas and must have considered its population significant enough to allow the residents to "borrow their gods" (presumably idols) to cure their king when the local gods were not forthcoming. It is believed that emigrants from mainland Greece, mainly from Thessaly, entered the island in the Late Bronze Age and bequeathed it with the Aeolic dialect of the Greek language, whose written form survives in the poems of Sappho, amongst others.

The abundant gray pottery ware found on the island and the worship of Cybele, the great mother-goddess of Anatolia, suggest the cultural continuity of the population from Neolithic times. When the Persian king Cyrus defeated Croesus (546 BC) the Ionic Greek cities of Anatolia and the adjacent islands became Persian subjects and remained such until the Persians were defeated by the Greeks at the Battle of Salamis (480 BC). The island was governed by an oligarchy in archaic times, followed by quasi-democracy in classical times. For a short period it was member of the Athenian confederacy, its apostasy from which is described in a stirring chapter of Thucydides's history of the Peloponnesian War. In Hellenistic times, the island belonged to various Macedonian kingdoms until 79 BC when it passed into Roman hands.

Important archaeological sites on the island are the Neolithic cave of Kagiani, probably a refuge for shepherds, the Neolithic settlement of Chalakies, and the extensive habitation of Thermi (3000–1000 BC). The largest habitation is found in Lisvori (2800–1900 BC) part of which is submerged in shallow coastal waters. There are also several archaic, classical Greek and Roman remains. Vitruvius called the ancient city of Mytilene "magnificent and of good taste". Remnants of its medieval history are three impressive castles.

Lesbos is the birthplace of several famous persons. In archaic times, Arion developed the type of poem called dithyramb, the progenitor of tragedy, Terpander invented the seven note musical scale for the lyre, followed by the lyric poet Alcaeus, and the most famous poetess Sappho. Phanias wrote history. The seminal artistic creativity of those times brings to mind the myth of Orpheus to whom Apollo gave a lyre and the Muses taught to play and sing. When Orpheus incurred the wrath of the god Dionysus he was dismembered by the Maenads and of his body parts his head and his lyre found their way to Lesbos where they have "remained" ever since. Pittacus was one of the Seven Sages of Greece. In classical times Hellanicus advanced historiography, Theophrastus, the father of botany, succeeded Aristotle as the head of the Lyceum. Aristotle and Epicurus lived there for some time, and it is there that Aristotle began systematic zoological investigations. In later times lived Theophanes, the historian of Pompey's campaigns, Longus wrote the famous novel Daphnis and Chloe, and much later the historian Doukas wrote the history of the early Ottoman Turks. In modern times the poet Odysseus Elytis, descendant of an old family of Lesbos received the Nobel Prize.

12 historic churches on the island were listed together on the 2008 World Monuments Fund's Watch List of the 100 Most Endangered Sites in the world. Exposure to the elements, outmoded conservation methods, and increased tourism are all threats to the structures. It is hoped that increased attention to their declining states will aid in their preservation.