In contrast to the views of Muhammad in Islam, the Christian views on him stayed highly negative during the Middle Ages for over a millennium. At this time, Christendom largely viewed Islam as a Christian heresy and Muhammad as a false prophet.

Various Western and Byzantine Christian thinkers considered Muhammad to be a perverted, deplorable man, a false prophet, and even the Antichrist, as he was frequently seen in Christendom as a heretic or possessed by demons. Some of them, like Thomas Aquinas, criticized Muhammad's promises of carnal pleasure in the afterlife.

With the Crusades of the High Middle Ages, and the wars against the Ottoman Empire during the Late Middle Ages, the Christian reception of Muhammad became more polemical, moving from the classification as a heretic to depiction of Muhammad as a servant of Satan or as the Antichrist, who will be eternally suffering tortures in Hell amongst the damned. By the Late Middle Ages, Islam was more typically grouped with Paganism, and Muhammad was viewed as an idolater inspired by the Devil. A more relaxed or benign view of Islam only developed in the modern period, after the Islamic empires ceased to be an acute military threat to Europe (see Orientalism).

The earliest written Christian knowledge of Muhammad stems from Byzantine sources, written shortly after Muhammad's death in 632 CE. In the anti-Jewish polemic the Teaching of Jacob, a dialogue between a recent Christian convert and several Jews, one participant writes that his brother "wrote to [him] saying that a deceiving prophet has appeared amidst the Saracens". Another participant in the Doctrina replies about Muhammad: "He is deceiving. For do prophets come with sword and chariot?, …[Y]ou will discover nothing true from the said prophet except human bloodshed". Though Muhammad is never called by his name, the author seems to know of his existence and represents both Jews and Christians as viewing him in a negative light. Other contemporary sources, such as the writings of Sophronius of Jerusalem, do not characterize Saracens as having their own prophet or faith, only remarking that the Saracen attacks must be a punishment for Christian sins.

Sebeos, a 7th-century Armenian bishop and historian, wrote shortly after the end of the first Arab civil war concerning Muhammad and his Farewell Sermon:

I shall discuss the line of the son of Abraham: not the one born of a free woman, but the one born of a serving maid, about whom the quotation from Scripture was fully and truthfully fulfilled: "His hands will be at everyone, and everyone will have their hands at him."... In that period a certain one of them, a man of the sons of Ishmael named Muhammad, a merchant, became prominent. A sermon about the Way of Truth, supposedly at God's command, was revealed to them, and [Muhammad] taught them to recognize the God of Abraham, especially since he was informed and knowledgeable about Mosaic history. Because the command had come from On High, he ordered them all to assemble together and to unite in faith. Abandoning the reverence of vain things, they turned toward the living God, who had appeared to their father, Abraham. Muhammad legislated that they were not to eat carrion, not to drink wine, not to speak falsehoods, and not to commit adultery. He said: "God promised that country to Abraham and to his son after him, for eternity. And what had been promised was fulfilled during that time when [God] loved Israel. Now, however, you are the sons of Abraham, and God shall fulfill the promise made to Abraham and his son on you. Only love the God of Abraham, and go and take the country which God gave to your father, Abraham. No one can successfully resist you in war, since God is with you.

Knowledge of Muhammad in Medieval Christendom became available after the early expansion of the Islamic religion in the Middle East and North Africa. In the 8th century John of Damascus, a Syrian monk, Christian theologian, and apologist that lived under the Umayyad Caliphate, reported in his heresiological treatise De Haeresibus ("Concerning Heresy") the Islamic denial of Jesus' crucifixion and his alleged substitution on the cross, attributing the origin of these doctrines to Muhammad himself:

And the Jews, having themselves violated the Law, wanted to crucify him, but having arrested him they crucified his shadow. But Christ, it is said, was not crucified, nor did he die; for God took him up to himself because of his love for him. And he [Muhammad] says this, that when Christ went up to heaven God questioned him saying "O Jesus, did you say that 'I am Son of God, and God'?" And Jesus, they say, answered: "Be merciful to me, Lord; you know that I did not say so, nor will I boast that I am your servant; but men who have gone astray wrote that I said this and they said lies concerning me and they have been in error". And although there are included in this scripture many more absurdities worthy of laughter, he insists that this was brought down to him by God.