Traditionally, it is believed that Mithridates II was the son of his predecessor Artabanus II, who died in battle against eastern enemies in ca 124 BC. However, new cuneiform and numismatic evidence suggests that Mithridates II was the youngest son of Phriapatius and succeeded Artabanus' young son, Arsaces X. At the time of his succession, the Parthian Empire was reeling from military pressures in the West and East. Several embarrassing defeats at the hands of eastern nomads had sapped the strength and prestige of the kingdom. However, Mithridates proved himself to be a capable king and was soon able to reincorporate Babylonia into the kingdom, which had been lost to Characene a short time before. As a sign of victory he had the coinage of Hyspaosines overstruck, although he had already died in 124 BC. The whole of Mesopotamia was taken in a rush and he reached Dura-Europus in 113 BC.
Mithridates II then attacked Armenia, then ruled by Artavasdes I and took hostage the Armenian king's son, the future Tigranes the Great. This was the first time that the Parthians actively interfered in Armenian politics.
In the east of the Empire, the situation seemed unsalvagable. Invading nomads (called Scythians in the Greek sources and Sakas in Indian sources) had destroyed the Greco-Bactrian Kingdom and greatly threatened the eastern borders of the empire. However, Mithridates was able to fend off the attacking nomads and reincorporate the provinces of Parthia and Aria back into the realm. He was able to make Sistan, which had come under the direct control of the nomads, a vassal at the very least.
In 121 BC the Chinese under Emperor Wu of Han had defeated the Xiongnu in the east and were expanding westwards in force. In Ferghana the Chinese sphere of influence encountered that of the Parthians. A Chinese delegation to the Parthian court is attested for the year 120 BC. In the following year the Silk Road was opened.
The Armenian King Tigranes I died in 95 BC and Mithridates put the Armenian heir Tigranes II, who had hitherto lived among the Parthians, on the Armenian throne. Soon after this Mithridates II attacked Adiabene, Gordyene and Osrhoene and conquered these city states, bringing the western border of the Parthian realm to the Euphrates. Here the Parthians encountered the Romans for the first time. In 96 BC Mithridates sent a certain Orobazos as an envoy to Sulla. Negotiation followed in which Sulla apparently gained the upper hand and Orobazos made himself and the Parthians look like suppliants. The actual result of the negotiations is not known, but it can be assumed that the border was set at the Euphrates. Orobazos would later be executed.
By the late 90s BC, Mithridates seems to have faced internal political issues. In 93/2 BC Mithridates' nephew, Sinatruces, rebelled in Susiana. He proclaimed himself king and held the region until 88/87 BC, at which point Mithridates' son, Gotarzes I, forced him to flee to the Central Asian steppe. Sinatruces later returned to the Parthian throne in 77/76 BC with the aid of Sakae mercenaries. Mithridates did not outlive the usurper and died in 91 BC.
There are clear signs that the Parthian empire was restructured under Mithridates II. The last administrative texts in cuneiform were written under his rule. Temples in the Babylonian style were replaced by some in a more Hellenic/Parthian style. Both facts seem to indicate that the temple administration system which dated back at least to Nebuchadnezzar II did not continue. The oldest documents yet discovered from Nisa belong to his reign.
The portrait of the king is almost exclusively known from his coinage. It is possible to identify several types of depiction in the coinage. He can be shown with a short beard and a diadem, but there are images which show him with a mid-length beard or with a long beard, still wearing the diadem. A completely different type of image shows him with a high domed tiara on his head.
At Mount Behistun, now in the west of Iran, there is a rock relief which shows the king and four vassals or officials, who make obesience to him. There are accompanying inscriptions in Greek. The relief is now in a bad state and known only from old copies.