The Legio V was one of the original twenty-eight legions raised by Octavian. There are two fifth legions recorded: the V Gallica and the V Urbana. It is possible that these both were early names for the V Macedonica. The legion probably participated in the Battle of Actium (31 BC). It later moved to Macedonia, where it stayed from 30 BC to AD 6, gaining its cognomen, before moving to Oescus (Moesia).
In 62, some vexillationes of the Fifth fought under Lucius Caesennius Paetus in Armenia against the Parthian Empire. 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 victorious war against the Parthians.
The Fifth was probably still in the East when the Great Jewish Revolt in Iudaea Province began in 66. Nero gave the V Macedonica, the X Fretensis and the XV Apollinaris to Titus Flavius Vespasianus to counter the revolt. 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. In the Year of the Four Emperors, 68, the legion stayed inactive in Emmaus, where several tombstones of soldiers of the V Macedonica remain. 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 (71). In 96, the later emperor Hadrian served the legion as tribunus militum.
In 101, the legion moved to Dacia, to fight in Trajan's campaign against the local populations. After the war ended in 106, the legion remained in Troesmis (modern Iglita), near the delta of the Danube since 107.
At the beginning of the reign of Commodus, the V Macedonica and the XIII Gemina defeated once again the Sarmatians, under the later usurpers Pescennius Niger and Clodius Albinus. The Fifth later supported Septimius Severus, in his fight for the purple.
While staying in Potaissa for most of the 3rd century, V Macedonica fought several times, earning honors. Valerian gave the Fifth the name III Pia III Fidelis; his son, Gallienus gave the legion the title VII Pia VII Fidelis, with the 4th, 5th and 6th titles awarded probably when the legion was used as a mobile cavalry unit against usurpers Ingenuus and Regalianus (260, Moesia). A vexillatio fought against Victorinus (Gaul, 269–271).
The legion returned to Oescus in 274, after Aurelian had retired from Dacia. It guarded the province in later centuries, becoming a comitatensis unit under the Magister Militum per Orientis. It probably became part of the Byzantine army.
The cavalry unit created by Gallienus was definitively detached by Diocletian, and become part of his comitatus. This unit was sent to Mesopotamia, where it successfully fought against the Sassanid Empire in 296, and then to Memphis, where it had to stay until its entering in the Byzantine army.