After the defeat of the Battle of Rhandeia, the whole V Macedonica, together with III Gallica, VI Ferrata, and X Fretensis under the command of Gnaeus Domitius Corbulo, was sent to the east to fight in the conclusion of the war.

In 67, in Galilee, the city of Sepphoris surrendered peacefully to the Roman army, and later the V Macedonica conquered Mount Gerizim, the chief sanctuary of the Samaritans.

After the proclamation of Vespasian as Emperor and the end of the war under his son Titus, the V Macedonica left Iudaea and returned to Oescus in 71.

A centurion of the legion, Calventius Viator, rose to prominence and was eventually promoted to commander of the emperor's horse guards, the equites singulares Augusti.

Based on a Roman inscription discovered near Betar, Hadrian removed the V Macedonica from Dacia (present-day Romania) and sent it to Provincia Iudaea, or what is Judea, along with Legio XI Claudia,[2] in order to put down an insurrection that broke out in the 16th year of his reign as Roman Emperor, while Tineius (Tynius) Rufus was governor of the province,[3] and which later became known as the Jewish Revolt under Bar Kokhba.

When Emperor Lucius Verus started his campaign against the Parthians (161–166), the legion moved to the east, but was returned to Dacia Porolissensis in 166 under Marcus Aurelius[4] with its basecamp in Potaissa to defend the Dacian provinces against the Marcomannic attacks and those of the Iazyges and the Quadi.

At the beginning of the reign of Commodus, the V Macedonica and the XIII Gemina once again defeated the Iazyges, under the later usurpers Pescennius Niger and Clodius Albinus.

Legio V Macedonica is mentioned again in the Notitia Dignitatum, stationed in Dacia Ripensis, with detachments in the Oriental Field Army and in Egypt.