In the Mamluk era, particularly in the 8th century AH, pandemics were prevalent. The overwhelming outbreak of plague in 749 AH was notable. Muslims responded to this plague diversely, based on their scientific specializations. This challenging epidemic prompted varied views among Muslim physicians. Notable figures including al-Shaqquri )d. 749/1348(, Ibn Khatimah )d. 770/1369(, and Lisan al-Din bin al-Khatib )d. 776/1374( presented their unique perspectives on the plauge. Muslim physicians’ efforts against the epidemic served as a precursor to modern medicine, despite facing challenges. These challenges arose from the persistent disease and skepticism within certain Islamic sects. This paper will focus on the examination of epidemic phenomenon in the 8th-century and clarify Muslim physicians’ efforts, resistance, and challenges during the process.