Peithon was the son of a Macedonian nobleman named Agenor and served as an officer in the army of Alexander the Great. He is first mentioned as the commander of a phalanx batallion in the story of Alexander's struggle against the Mallians (Indian Mâlava), who lived in the southern Punjab (January 325). Peithon captured a city and killed the refugees in a nearby forest.
When the Macedonians had reached the confluence of the Acesines and the Indus, he built a new town -Alexandria, now Chachran- and decided that all country between this city and the Ocean, together with the coast of the Ocean, would belong to a new satrapy. Peithon was made satrap. Oxyartes, the father of queen Roxane, seems to have been involved in the government of the region as well.
Peithon oversaw the building of other towns and commanded the rearguard of the Macedonian army. In this function, he attacked king Musicanus (Indian Mûshika), who had joined a large rebellion in April 325. The Indian ruler was sent to Alexander, who had him crucified. The revolt, however, was widespread, and the satrap of the Punjab, Philip, was killed.
During the summer, Peithon was in the southern part of his satrapy, where Alexander and his admiral Nearchus were preparing the return to the west in a new city named Patala. The satrap arrived in July. A month later, Alexander left India and started to march home. This gave new courage to the neighboring tribes, the Oreitans (Persian Barikânu, 'mountain people'), who attacked the base of Nearchus and forced him to leave in September, at an unfavorable moment.
Peithon's army, outnumbered by the Oreitans, went to the north. Our sources say that he was appointed as satrap of the Punjab, but it is easy to see that the Macedonians were forced to give up their conquests in the southern valley of the Indus. As satrap of the Punjab, Peithon cooperated with two local kings, Taxiles and Porus. He was confirmed in this office by the regents who reigned after Alexander: Perdiccas (323-320) and Antipater (320-319).
In 317, one of Alexander's successors, Peithon the satrap of Media, tried to subdue the leaders of the eastern provinces. The other satraps united and offered resistance. Many Macedonians left India and marched to the west, and Porus, who was unwilling to assist, was murdered. The situation in the Punjab was confused after the removal of a loyal ruler and the troops, and the king of Magadha (the Ganges valley), Sandracottus (Chandragupta Maurya), conquered the Indus valley. This meant the end of the Macedonian empire in the east, less than ten years after the invasion.
Peithon went to the west as well. Here, one of Alexander's generals, Antigonus Monophthalmus, was trying to keep the empire united, with himself as sole ruler. He appointed Peithon as satrap of Babylonia (315). In the next year, war broke out between Antigonus and his enemies Cassander and Ptolemy. Antigonus sent his son Demetrius to Palestine, where he had to prevent Ptolemy from attacking Phoenicia and Syria. Together with Alexander's former admiral Nearchus, Peithon was added to Demetrius' staff. The two armies met at Gaza in the Autumn of 312, where the Egyptian army was victorious; Antigonus' son managed to escape, but the satrap of Babylonia was killed in action.
One result was the absence of a satrap at Babylon, which made it easy for Ptolemy's ally Seleucus to capture the city in May 311.