Ptolemy succeeded in 180 at the age of about 12 and ruled jointly with his mother, Cleopatra I, until her death in 176 BC. The following year he married his sister, Cleopatra II.

In 170 BC, Antiochus IV began the sixth Syrian War and invaded Egypt twice. He was crowned as its king in 168, but abandoned his claim on the orders of the Roman Senate. From 169-164 Egypt was ruled by a triumvirate consisting of Ptolemy, his sister-queen and his younger brother known as Ptolemy VIII Physcon, but in 164 he was driven out by his brother and went to Rome to seek support, which he received from Cato. He was restored the following year by the intervention of the Alexandrians and ruled uneasily, cruelly suppressing frequent rebellions. In 152 BC he briefly ruled jointly with one of his sons, known as Ptolemy Eupator, but it is thought that Ptolemy Eupator died that same year.

He is reputed to have taken as eromenos a boy named Galestes, whom he loved not only for his good looks but also for his wisdom. (Aelian, Varia Historia, I.30) Ptolemy VI Philometer was killed in Syria, fighting against Alexander Balas.