He was a minor when his father died, but the date of his accession cannot be determined. It seems probable that it must have taken place well before 240 BC, as Memnon tells us that he was a child at his father's death, and he had a daughter of marriageable age in 222 BC. Shortly after his accession, his kingdom was invaded by the Gauls, who were eventually repulsed.
After Mithridates attained manhood, he married Laodice, a sister of Seleucus II Callinicus, with whom he is said to have received the province of Phrygia as a dowry. Despite this alliance, Mithridates II fought against Seleucus during a war between Seleucus and Antiochus Hierax. Eventually, Mithridates defeated Seleucus in a great battle at Ancyra in 235 BC whereby Seleucus lost twenty thousand of his troops and narrowly escaped with his own life. In 222 BC, Mithridates gave his daughter Laodice in marriage to the Seleucid king Antiochus III. Another of his daughters, also named Laodice, was married about the same time to Achaeus, the cousin of Antiochus.
In 220 BC, Mithridates declared war upon the wealthy and powerful city of Sinope. However, he was unable to weaken it and the city did not come under the control of the kings of Pontus until 183 BC.
Earlier in his rule, Mithridates II vied with the other monarchs of Asia in sending magnificent presents to the Rhodians, after the destruction of their city by an earthquake in 227 BC. The date of his death is unknown. He was succeeded by Mithridates III, his son with Laodice.