The decline in civic virtue between the times of the Roman Republic and late Imperial Rome is one of Gibbon's primary themes. He saw the foreign population in Rome and the legion's adoption of foreign cultural values while serving abroad as leading to cultural decline and decadence at home. He believed this cultural decadence contributed to the fall of Rome.

Economic decline is another of Gibbon's main themes. Some of the drivers Gibbon emphasizes are the high cost associated with military overextension; the high cost of maintaining the imperial infrastructure of bridges, roads, and aqueducts; the progressive debasement of the currency with base metals and the resulting inflation; high taxation of the citizens; extreme wealth concentration at the top; and rampant corruption in the late imperial administration.

The theme of a deluge of foreign immigrants and barbarian invaders finally overwhelming the already culturally and economically weakened empire was significant, according to Gibbon. Germanic settlers were given permission to settle within the empire in large numbers and, in many cases, served in the Roman army as mercenaries. Many of these foreign mercenaries eventually turned on Rome rather than defending the empire. Waves of Huns, Mongols, Franks, Visigoths, Ostrogoths, and many other tribes attacked and invaded the borders of the empire until the borders finally collapsed.

The decline of the comparatively tolerant and philosophical classical religion and the rise of an ultimately intolerant Christianity within the empire is another prominent theme of Gibbon. Gibbon thought the otherworldly, meek, submissive, monastic, and anti-aristocratic values of Christianity sapped the empire of much of its earlier energetic vitality, paving the way for its collapse.

The Islamic invasion is another prominent theme in Gibbon's work. The Islamic invasion quickly swallowed up all of Roman Syria, Roman Palestine, Roman Egypt, and Roman North Africa, severely disrupting Mediterranean and eastern trade routes and even safe access to the Mediterranean. With the fall of Roman Asia Minor to Islam, the way was open for the Islamic invasion of Europe from the east. Gibbon believed Islam was a man-made religion because of what he considered to be the obviously plagiarized contents of the Koran.