The city was heavily fortified and according to the Greek historian Appian, had thick and towering walls that stood 25 meters high, providing a formidable defence against a prolonged siege. Tigranocerta was still an unfinished city when Lucullus laid siege to it in the late summer of 69. Lucullus chose not to pursue Tigranes while he had an unimpeded path towards Tigranocerta he advanced and began to lay siege to it. Lucullus' legates were able to disrupt two separate detachments coming to the aid of Tigranes, and even located and engaged the king's forces in a canyon in the Taurus. Learning of Mithrobarzanes' defeat, Tigranes entrusted the defence of his namesake city to Mancaeus and left to recruit a fighting force in the Taurus Mountains. Unable to reconcile with this reality for a certain period of time, he belatedly sent a general named Mithrobarzanes with 2,000–3,000 cavalrymen to slow down Lucullus' advance, but his forces were cut to pieces and routed by the 1,600 cavalry led by Sextilius, one of the legates serving under Lucullus. Tigranes, who was residing at Tigranocerta in the summer of 69, was not only astonished by the speed of Lucullus' rapid advance into Armenia but by the fact that he had even launched such an operation in the first place.
In the summer of 69, he marched his troops across Cappodocia and the Euphrates river and entered the Armenian province of Tsop'k', where Tigranocerta was located. Although he had no mandate from the Senate to authorize such a move, he attempted to justify his invasion by distinguishing as his enemy king Tigranes and not his subjects. Lucullus was astonished upon hearing this in the year 70, and he began to prepare for an immediate invasion of Armenia. Tigranes refused Appius Claudius' demands, stating that he would prepare for war against the Republic.
Lucullus sent an ambassador named Appius Claudius to Antioch to demand that Tigranes surrender his father-in-law should he refuse, Armenia would face war with Rome. Friction between the two had existed for several decades, although it was during the Third Mithridatic War that the Roman armies under Lucullus made significant progress against Mithridates, forcing him to take refuge with Tigranes.
This period of Armenian hegemony in the region, however, was coming close to an end with a series of Roman victories in the Roman–Mithridatic Wars. The city soon became the king's headquarters in Syria and flourished as a great centre for Hellenistic culture, complete with theatres, parks and hunting grounds.
In Syria, he began the construction of the city of Tigranocerta (also written Tigranakert), which he named after himself, and imported a multitude of peoples, including Arabs, Greeks, and Jews, to populate it. With his father-in-law and ally securing the empire's western flank, Tigranes was able to conquer territories in Parthia and Mesopotamia and annex the lands of the Levant. Tigranes' expansion into the Near East led to the creation of an Armenian empire that stretched almost across the entire region. After the Romans defeated the Armenian cataphracts, the balance of Tigranes' army, which was mostly made up of raw levies and peasant troops from his extensive empire, panicked and fled, and the Romans remained in charge of the field. Feigning retreat, the Romans crossed at a ford and fell on the right flank of the Armenian army. Having laid siege to Tigranocerta, the Roman forces fell back behind a nearby river when the large Armenian army approached. Mithridates fled to seek shelter with his son-in-law, and Rome invaded the Kingdom of Armenia. The battle arose from the Third Mithridatic War being fought between the Roman Republic and Mithridates VI of Pontus, whose daughter Cleopatra was married to Tigranes. The Roman force, led by Consul Lucius Licinius Lucullus, defeated Tigranes, and as a result, captured Tigranes' capital city of Tigranocerta. The Battle of Tigranocerta (Armenian: Տիգրանակերտի ճակատամարտ, Tigranakerti tchakatamart) was fought on 6 October 69 BC between the forces of the Roman Republic and the army of the Kingdom of Armenia led by King Tigranes the Great.