Marcus Licinius Crassus, one of the triumvirs, who was now proconsul of Syria, invaded Parthia in 53 BCE in belated support of Mithridates. As his army marched to Carrhae (modern Harran, southeastern Turkey), Orodes II invaded Armenia, cutting off support from Rome's ally Artavasdes II of Armenia (r. 53–34 BCE). Orodes persuaded Artavasdes to a marriage alliance between the crown prince Pacorus I of Parthia (d. 38 BCE) and Artavasdes' sister.

Surena, with an army entirely on horseback, rode to meet Crassus. Surena's 1,000 cataphracts (armed with lances) and 9,000 horse archers were outnumbered roughly four to one by Crassus' army, comprising seven Roman legions and auxiliaries including mounted Gauls and light infantry. Using a baggage train of about 1,000 camels, the Parthian army provided the horse archers with a constant supply of arrows. The horse archers employed the "Parthian shot" tactic: feigning retreat to draw enemy out, then turning and shooting at them when exposed. This tactic, executed with heavy composite bows on the flat plain, devastated Crassus' infantry.

With some 20,000 Romans dead, approximately 10,000 captured, and roughly another 10,000 escaping west, Crassus fled into the Armenian countryside. At the head of his army, Surena approached Crassus, offering a parley, which Crassus accepted. However, he was killed when one of his junior officers, suspecting a trap, attempted to stop him from riding into Surena's camp. Crassus' defeat at Carrhae was one of the worst military defeats of Roman history. Parthia's victory cemented its reputation as a formidable if not equal power with Rome. With his camp followers, war captives, and precious Roman booty, Surena traveled some 700 km (430 mi) back to Seleucia where his victory was celebrated. However, fearing his ambitions even for the Arsacid throne, Orodes had Surena executed shortly thereafter.