Dating from the eastern conquests of Licinius Lucullus and Pompey Magnus in the 60's BC and into the imperial period, Roman expansion made conflict with Parthia inevitable. During the reign of Nero (50's - 60's AD), a major campaign to ensure Roman hegemony over Armenia was conducted under Cnaeus Domitius Corbulo. Though the war between Rome and Parthia largely resulted in a stalemate, the matter was settled by allowing Rome the final authority in naming the Armenian King. Despite the settlement the situation remained problematic for the better part of the next half century and during Trajan's reign matters of Armenian succession flared into war again.

By AD 113, the Parthian King Osroes I (in the midst of an internal conflict with rival King Vologases III) had deposed the Armenian King in favor of his own nephew (likely to strengthen his position within the Parthian borders), breaking the already tenuous peace between Rome and Parthia. Trajan's reaction was swift and he moved east from Rome while preparing an invasion force. Failed attempts to broker a peace by the Parthians before any impending Roman invasion led to understandable contemporary speculation that Trajan's true motive was an Alexandrian style campaign of conquest, and political events simply offered a convenient excuse. Regardless of Trajan's personal motivation for going to war he marched into Armenia in AD 114. Initial resistance was weak and ineffective (perhaps an indication of the debilitating internal struggle in Parthia); Armenia's royalty was deposed and its independence stripped with its annexation as a Roman province.

Over the following two years, Trajan moved south from Armenia directly into Parthian territory. Militarily, his campaign was met with great success and resistance in the field was ineffective. With the capture of such cities and Babylon and the Parthian capital of Ctesiphon on the Euphrates and Tigris Rivers, Mesopotamia and Assyria (essentially comprising modern Iraq) were annexed as Roman provinces and the emperor received the title Parthicus. Trajan continued his march to the southeast, eventually reaching the Persian Gulf in AD 116. Though Dio Cassius reports that Trajan would have preferred to march in the footsteps of Alexander, his advanced age (approximately 63 years) and slowly failing health forced him to abandon any such thoughts.

Despite the swiftness of the initial victories, the long term prospects for Roman control were completely in doubt. Returning to the west and crossing the Tigris, Trajan stopped to lay siege to the desert town of Hatra. In AD 117, with poor supply and unable to breach the walls, the Romans suffered their first defeat of the campaign with Trajan narrowly avoiding personal injury. To add insult to the defeat, the recently 'conquered' population of Jewish inhabitants began to revolt against newly installed Roman rule. For reasons that aren't entirely clear, though religion certainly played a major part, the revolt spread to Jews living in Egypt, Cyrene and Cyprus.

The massacre of Roman citizens on a massive scale by armed Jewish mobs in Cyprus (recorded as 240,000) and Cyrene as well as the destruction of pagan temples forced brutal retaliation. Massacre was met with massacre as Trajan ordered legionary response to the uprising. Jews were virtually expelled from Cyprus and the population of North Africa (Jewish, Roman and Greek) was decimated. The revolt and its suppression dragged on even into the reign of Hadrian (who would be faced years later with another considerable Jewish uprising in Judaea), but Trajan still yearned for his Alexander style eastern campaign and exacting revenge against the people of Hatra. A planned renewal of the offensive was brought to a halt as the emperor fell ill during the summer of AD 117, and Trajan began the trip back to Rome. Landing in Cilicia after a short journey by sea, the emperor died in Selinus on August 9 most likely of natural causes.

Trajan, having no children of his own, had never settled the matter of succession, but Hadrian (the son of Trajan's cousin) had long held a favored position with the Empress Plotina. Though the official word was that Trajan adopted Hadrian on his death bed, rumor had it that the choice was made only after the emperor's death. Regardless, it was Hadrian who was left in command in the east after Trajan fell ill and the matter of his succession was uncontested (and abruptly gave up all of the eastern territorial gains). Trajan, who had held the same level of power as such predecessors as Domitian, wielded it with far less strict authority and won the admiration of both the masses and aristocracy. He was quickly deified by the Senate and Trajan's greatness was recognized for centuries to come. Each successive emperor even through to the Christian era of the late 4th century AD, was blessed with the prayer 'felicior Augusto, melior Traiano', or (may he be) 'more fortunate than Augustus and better than Trajan.'