Under Ariarathes IV, Cappadocia first came into contact with the Roman Republic as a foe allied to the Selecuid King Antiochus the Great during the Roman–Seleucid War from 192 to 188 BC.

Following Rome's victory over Antiochus, Ariarathes IV entered friendly relations with the Republic by betrothing his daughter to the king of Pergamum, a Roman ally.

In 130 BC, Cappadocian king Ariarathes V supported the Roman Consul Publius Licinius Crassus Dives Mucianus in his failed attempt to overthrow Eumenes III.

Mithridates VI swiftly invaded, expelling Nicomedes III from the region, restoring his nephew Ariarathes VII to the Cappadocian throne, and returning Cappadocia to Pontus's sphere of influence.

In 89 BC, after having made peace arrangement with Rome and with Ariobarzanes I restored to the Cappadocian throne, Mithridates VI again invaded Cappadocia, reinstalling his son Ariarathes IX as puppet-king under Pontic rule.

With Mirthidates VI again having designs on Roman protectorates in Asia Minor, including Cappadocia, Rome launched the Third Mithridatic War to end the Pontic threat.

Mithridates VI was then forced to flee north across the Black Sea to the Bosporan Kingdom under the rule of his son Machares, bringing the war to an effective end in 65 BC.

While Mithridates VI was eager to fight the Romans once more, his youngest son Pharnaces II of Pontus was not and plotted to remove his father from power.

With Mithridates VI absent from Asia Minor, Pompey officially annexed Bithynia, Pontus, and Cilicia in the Roman Republic as provinces.

With Armenia reduced, Pompey then traveled south and officially annexed the Roman client kingdom of Syria in the Republic as a province by deposing its king Antiochus XIII Asiaticus.

When Julius Caesar crossed the Rubicon River in 49 BC and started his civil war, many members of the Roman Senate under the leadership of Pompey fled to the East.

The rulers of Cappadocia and Galatia, Ariobarzanes III and Deiotarus respectively, appealed to Calvinus for protection and soon the Roman forces sought battle with Pharnaces II.

They met at the Battle of Nicopolis in eastern Anatolia, where Pharnaces II defeated the Roman army and overran much of Cappadocia, Pontus, and Bithynia.

After the defeating the Ptolemaic forces at the Battle of the Nile, Caesar left Egypt in 47 BC and travelled through Syria, Cilicia, and Cappadocia to face Pharnaces II.

Caesar met Pharnaces II at the Battle of Zela, decisively defeating the Pontic king and reassessing Roman dominance over Asia Minor.

Caesar then incorporated Lesser Armenia into Cappadocia to serve as a buffer from Rome's interests in Asia Minor against future Eastern aggression.

Caesar was assassinated on March 15, 44 BC, by the members of the Roman Senate, Marcus Junius Brutus and Gaius Cassius Longinus chief among them.

When Ariobarzanes III objected to the level of Roman intervention into his kingdom, Cassius had him executed and installed his younger brother Ariarathes X upon the Cappadocian throne in 42 BC.

Augustus gave Archelaus these additional territories in order to eliminate piracy in the Eastern Mediterranean and to build a buffer between Rome and the Parthian Empire.

Years earlier, Tiberius had been slighted by Archelaus when the Cappadocian king showed favor to Gaius Caesar, one of Augustus's grandsons and chief heirs.

Sending his adoptive son Germanicus to oversee Rome's affairs in the East, Tiberius then annexed Cappadocia directly into the Empire by reducing the kingdom into a Roman province.

Under orders from the Emperor, Germanicus also annexing Cappadocia's southeastern neighbor, the client kingdom of Commagene, into the Empire as a part of the province of Syria.

However, in 62 AD, the Roman Emperor Nero deposed him and annexed his kingdom into direct imperial ruled by incorporating his former territory into Cappadocia.

As a Senatorial province during the middle of the second century AD, Cappadocia retained a permanent military garrison of three legions and several auxiliary units, totally over 28,000 troops.

The military presence in Cappadocia served as an important response force against invasions from the Parthian Empire and allowed the Roman's easy intervention into the affairs of their client kingdom of Armenia.

The first Cappadocian to be admitted to the Roman Senate was Tiberius Claudius Gordianus, during the reign of Marcus Aurelius during the middle second century AD.

On the highway between Constantinople and Antioch Caesarea saw a significant number of imperial visits (Itineraries of the Roman emperors, 337–361); Valens (363–378) was particularly frequent.