He was installed as Sultan of Johor in 1564 by the Acehnese upon the death of his father, Sultan Alauddin Riayat Shah II, who died shortly after he was captured and brought back to Aceh after the Acehnese invasion of Johor.
Muzaffar II moved his capital to Seluyut in 1565 from Johor Lama to assert his independence from the Acehnese.
He died of poison in 1570 and was succeeded by Sultan Abdul Jalil Shah I.
His third wife was the former wife of Sultan Ali Jalla Abdul Jalil Shah II and daughter of Sultan Husain Ali Riayat Shah of Aceh.
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