In about 335 BC, Alexander departed for his Asiatic campaign, and Aristotle, who had served as an informal adviser (more or less) since Alexander ascended the Macedonian throne, returned to Athens and opened his own school of philosophy. He may, as Aulus Gellius says, have conducted a school of rhetoric during his former residence in Athens; but now, following Plato's example, he gave regular instruction in philosophy in a gymnasium dedicated to Apollo Lyceios, from which his school has come to be known as the Lyceum. (It was also called the Peripatetic School because Aristotle preferred to discuss problems of philosophy with his pupils while walking up and down -- peripateo -- the shaded walks -- peripatoi -- around the gymnasium.)

During the thirteen years (335 BC–322 BC) which he spent as teacher of the Lyceum, Aristotle composed most of his writings. Imitating Plato, he wrote "Dialogues" in which his doctrines were expounded in somewhat popular language. He also composed the several treatises (which will be mentioned below) on physics, metaphysics, and so forth, in which the exposition is more didactic and the language more technical than in the "Dialogues". These writings show to what good use he put the resources Alexander had provided for him. They show particularly how he succeeded in bringing together the works of his predecessors in Greek philosophy, and how he pursued, either personally or through others, his investigations in the realm of natural phenomena. Pliny claimed that Alexander placed under Aristotle's orders all the hunters, fishermen, and fowlers of the royal kingdom and all the overseers of the royal forests, lakes, ponds and cattle-ranges, and Aristotle's works on zoology make this statement more believable. Aristotle was fully informed about the doctrines of his predecessors, and Strabo asserted that he was the first to accumulate a great library.

During the last years of Aristotle's life the relations between him and Alexander the Great became very strained, owing to the disgrace and punishment of Callisthenes whom Aristotle had recommended to Alexander. Nevertheless, Aristotle continued to be regarded at Athens as a friend of Alexander and a representative of Macedonia. Consequently, when Alexander's death became known in Athens, and the outbreak occurred which led to the Lamian war, Aristotle shared in the general unpopularity of the Macedonians. The charge of impiety, which had been brought against Anaxagoras and Socrates, was now, with even less reason, brought against Aristotle. He left the city, saying (according to many ancient authorities) that he would not give the Athenians a chance to sin a third time against philosophy. He took up residence at his country house at Chalcis, in Euboea, and there he died the following year, 322 BC. His death was due to a disease, reportedly 'of the stomach', from which he had long suffered. The story that his death was due to hemlock poisoning, as well as the legend that he threw himself into the sea "because he could not explain the tides," is without historical foundation.

Very little is known about Aristotle's personal appearance except from hostile sources. The statues and busts of Aristotle, possibly from the first years of the Peripatetic School, represent him as sharp and keen of countenance, and somewhat below the average height. His character—as revealed by his writings, his will (which is undoubtedly genuine), fragments of his letters and the allusions of his unprejudiced contemporaries—was that of a high-minded, kind-hearted man, devoted to his family and his friends, kind to his slaves, fair to his enemies and rivals, grateful towards his benefactors. When Platonism ceased to dominate the world of Christian speculation, and the works of Aristotle began to be studied without fear and prejudice, the personality of Aristotle appeared to the Christian writers of the 13th century, as it had to the unprejudiced pagan writers of his own day, as calm, majestic, untroubled by passion, and undimmed by any great moral defects, "the master of those who know".