很多人认为君士坦丁一世(公元306-337年在位)是第一个“拜占庭皇帝”。是他于公元324年把帝国首都从尼克美狄亚迁到拜占庭，并把后者重建为君士坦丁堡，也称Nova Roma(“新罗马”)。罗马城本身从戴克里先治下开始就不再作为帝国首都。有人把帝国的起源追溯到狄奥多西一世统治时（379年-395年）和基督教正式取代罗马异教，或者从他395年去世时东西方政治永久性分裂算起。其他人将其定为之后的476年，传统上认为的最后一个西罗马皇帝罗慕路斯·奥古斯都被废黜时，只剩下东方希腊化地区的皇帝作为帝国的唯一权威。也有人认为是希拉克略在位时（约620年）的帝国改组，拉丁文的头衔和使用被正式改为希腊文。无论如何，这种转变是逐渐的，至330年君士坦丁在他的新首都举行落成典礼时，希腊化和不断深入的基督教化已经开始。一般认为帝国于君士坦丁堡1453年陷落于鄂图曼土耳其帝国后灭亡。
公元541-541年，全国流行的查士丁尼大瘟疫折磨着拜占庭帝国，包括它的首都君士坦丁堡。据估计查士丁尼大瘟疫使全世界1亿人丧生。它使541年至700年间的欧洲人口减少约50%，可能也是阿拉伯人征服成功的原因之一。
Many consider Emperor Constantine I (reigned 306–337) to be the first "Byzantine Emperor". It was he who moved the imperial capital in 324 from Nicomedia to Byzantium, refounded as Constantinople, or Nova Roma ("New Rome"). The city of Rome itself had not served as the capital since the reign of Diocletian. Some date the beginnings of the Empire to the reign of Theodosius I (379–395) and Christianity's official supplanting of the pagan Roman religion, or following his death in 395, when the political division between East and West became permanent. Others place it yet later in 476, when Romulus Augustulus, traditionally considered the last western Emperor, was deposed, thus leaving sole imperial authority with the emperor in the Greek East. Others point to the reorganization of the empire in the time of Heraclius (ca. 620) when Latin titles and usages were officially replaced with Greek versions. In any case, the changeover was gradual and by 330, when Constantine inaugurated his new capital, the process of hellenization and increasing Christianization was already under way. The Empire is generally considered to have ended after the fall of Constantinople to the Ottoman Turks in 1453. The Plague of Justinian was a pandemic that afflicted the Byzantine Empire, including its capital Constantinople, in the years 541–542. It is estimated that the Plague of Justinian killed as many as 100 million people across the world. It caused Europe's population to drop by around 50% between 541 and 700. It also may have contributed to the success of the Arab conquests.