Having distinguished himself in his father's war against the Seljuk Turks, he was nominated emperor in preference to his elder surviving brother. Endowed with a fine physique and great personal courage, he devoted himself whole-heartedly to a military career. He endeavoured to restore by force of arms the predominance of the Byzantine Empire in the Mediterranean countries, and so was involved in conflict with his neighbours on all sides.
In 1144 he brought back Raymond of Antioch to his allegiance, and in the following year drove the Seljuk Turks out of Isauria. In 1147 he granted a passage through his dominions to two armies of the Second Crusade under Conrad III of Germany and Louis VII of France; but the numerous outbreaks of overt or secret hostility between the Franks and the Greeks on their line of march, for which both sides were to blame, nearly precipitated a conflict between Manuel and his guests.
In the same year the emperor made war upon Roger II of Sicily, whose fleet captured Corfu and plundered the Greek towns, but in 1148 was defeated with the help of the Venetians. In 1149 Manuel recovered Corfu and prepared to take the offensive against the Normans. With an army mainly composed of mercenary Italians he invaded Sicily and Apulia, and although the progress of both these expeditions was arrested by defeats on land and sea, Manuel maintained a foothold in southern Italy, which was secured to him by a peace in 1155, and continued to interfere in Italian politics.
In his endeavour to weaken the control of Venice over the trade of his empire he made treaties with Pisa and Genoa; to check the aspirations of Frederick I, Holy Roman Emperor he supported the free Italian cities with his gold and negotiated with Pope Alexander III. In spite of his friendliness towards the Roman church Manuel was refused the title of "Augustus" by Alexander, and he nowhere succeeded in attaching the Italians permanently to his interests. Nonetheless in a war with the Venetians he not only held his ground in Italy but drove his enemies out of the Aegean Sea.
On his northern frontier Manuel forced the rebellious Serbs to vassalage (1150-1152) and made repeated attacks upon the Hungarians with a view to annexing their territory along the Sava. In the wars of 1151-1153 and 1163-1168 he led his troops into Hungary but failed to maintain himself there; in 1168, however, a decisive victory near Zemun enabled him to conclude a peace by which Dalmatia and other frontier strips were ceded to him.
In 1169 he sent a joint expedition with King Amalric I of Jerusalem to Egypt, which retired after an ineffectual attempt to capture Damietta. In 1158-1159 he fought with success against Raymond of Antioch and the Seljuk Turks, but in later wars against the latter he made no headway. In 1176 he was decisively defeated by them in the pass of Myriokephalon, where he allowed himself to be surprised in line of march. This disaster, though partly retrieved in the campaign of the following year, had a serious effect upon his vitality; henceforth he declined in health and in 1180 succumbed to a slow fever.
In spite of his military prowess Manuel achieved but in a slight degree his object of restoring the Byzantine Empire. In fact he succeeded in unifying almost all his neighbors in common hatred as enemies, rather than playing one foe against the other. His victories were counterbalanced by numerous defeats, sustained by his subordinates, and his lack of statesmanlike talent prevented his securing the loyalty of his subjects. The expense of keeping up his mercenary establishment and the sumptuous magnificence of his court put a severe strain upon the financial resources of the state. The subsequent rapid collapse of the Byzantine Empire was largely due to his brilliant but unproductive reign.
Manuel married, firstly, a sister-in-law of Conrad III of Germany; and secondly, a daughter of Raymond of Antioch, Maria (renamed Xena upon their marriage). His successor, Alexius II Comnenus, was a son of the latter.