According to Ctesias, who is not especially reliable but is often our only source, Amytis, wife of Megabyzus and daughter of Xerxes, was accused of adultery shortly thereafter. As such, Megabyzus took part in the conspiracy of Artabanus to assassinate the emperor, but betrayed him before he could kill the new emperor Artaxerxes as well. In a battle, Artabanus' sons were killed and Megabyzus was wounded, but Amytis interceded on his behalf and he was cured.
After this Megabyzus became satrap of Syria. Together with Artabazus, satrap of Phrygia, he had command of the Persian armies sent to put down the revolt of Inarus in Egypt. They arrived in 456 BC, and within two years had put down the revolt, capturing Inarus and various Athenians supporting him. They then turned their attention to Cyprus, which was under attack by the Athenians, led by Cimon. Shortly thereafter hostilities between Persia and Athens ceased, called the peace of Callias.
Some time thereafter, Megabyzus himself revolted. Ctesias tells us the reason was that Amestris had the captives from the Egyptian revolt executed, though Megabyzus had given his word that they would not be harmed. Armies under Usiris of Egypt and then Menostanes of Babylon were sent against him, both foregoing battle for (non-fatal) duels between the generals, and in both cases Megabyzus was victorious. His honour restored, Megabyzus agreed to surrender and was pardoned, retaining his position. Some time later, Megabyzus saved Artaxerxes from a lion in a hunt, was subsequently exiled to Cyrtae for violating the royal prerogative to make the first kill, but returned to Susa by pretending to be a leper and was pardoned.
Megabyzus died shortly thereafter, at age 76. His son Zopyrus is known to have visited Athens, and aided in its assault on Caunus during his father's exile, where he was killed by a rock.