After the death of Plato (347 BC), Aristotle was considered as the next head of the Academe, a post that was eventually awarded to Plato's nephew. Aristotle then went with Xenocrates to the court of Hermias, ruler of Atarneus in Asia Minor, and married his niece and adopted daughter, Pythia. In 344 BC, Hermias was murdered in a rebellion (or a Persian attack?), and Aristotle went with his family to Mytilene.

It is also reported that he stopped on Lesbos and briefly conducted biological research. Then, one or two years later, he was summoned to his native Stageira by King Philip II of Macedon to become the tutor of Alexander the Great, who was then 13.

Plutarch wrote that Aristotle not only imparted to Alexander a knowledge of ethics and politics, but also of the most profound secrets of philosophy. We have much proof that Alexander profited by contact with the philosopher, and that Aristotle made prudent and beneficial use of his influence over the young prince (although Bertrand Russell disputes this). Due to this influence, Alexander provided Aristotle with ample means for the acquisition of books and the pursuit of his scientific investigation.

It is possible that Aristotle also participated in the education of Alexander's boyhood friends, which may have included for example Hephaestion and Harpalus. Aristotle maintained a long correspondence with Hephaestion, eventually collected into a book, unfortunately now lost.

According to sources such as Plutarch and Diogenes, Philip had Aristotle's hometown of Stageira burned during the 340s BC, and Aristotle successfully requested that Alexander rebuild it. During his tutorship of Alexander, Aristotle was reportedly considered a second time for leadership of the Academy; his companion Xenocrates was selected instead.