In the aftermath of the Roman–Parthian War of 58–63, Emperor Nero levied the I Italica with the name phalanx Alexandri Magni ("phalanx of Alexander the Great"), for a campaign in Armenia, ad portas Caspias - to the pass of Chawar. The sources mention the peculiar fact that the original legionaries were Italics, all over six feet tall. However, since the Jewish Revolt broke out a few weeks later, the projected Armenian campaign never took place. Also, the governor of Gaul, Gaius Julius Vindex, rose in revolt in early 68 and I Italica was redirected there, arriving just in time to see the end of the revolt. In the Year of the Four Emperors (69), after the death of Nero, the legion received the name I Italica and fought for Vitellius at the second Battle of Bedriacum, where the Vitellians were defeated by forces supporting Vespasian. The new emperor sent I Italica to the province of Moesia in 70. They encamped at Novae (modern Svishtov) which became the legions provincial base for centuries.

The legion served on campaign during the Dacian wars of Trajan. The legion was also responsible for bridge construction over the Danube. Building activities seem to have been an area of expertise for the legion. Around 140, a centurion from I Italica was responsible for the construction of a section of the Antonine Wall.