The 21st century is witnessing a war between mankind and microorganisms. The worldwide outbreak of infectious diseases is responsible for morbidity and mortality. The pharmaceutical industry has limited drugs in the pipeline against infectious diseases. Resistance of microorganisms against already available drugs is another concern. An initiative from researchers to search for new ways to prevent or treat infectious diseases is necessary. Many herbal drugs are known to be effective against pathogenic organisms from ancient times. Repurposing of herbal medicines for infectious diseases is a prodigious initiative. Azadirachta indica, commonly known as neem, is known to be effective against infectious diseases from ancient times. It is a member of the Meliaceae family. Leaves, seeds, fruits, and roots of this plant are reported to be effective according to Chinese, Ayurvedic, and Unani medicine. The plant has antiviral, antibacterial, and antifungal properties. The principal component of neem is azadirachtin. Other constituents, namely nimbolinin, nimbin, nimbidin, nimbidol, are also known to be having medicinal properties. Antibacterial and antifungal properties can be attributed to azadirachtin, quercetin, ß-sitosterol, gedunin, and polyphenolic flavonoids. Many pharmacological studies report antimicrobial efficacy of Azadirachta indica. The present chapter will explain the link between phytochemical constituents of neem to antimicrobial activity along with possible underlying mechanisms and pathways. Clinical studies on neem are also discussed in great detail to highlight the emergence of this traditional medicine into modern medicine in the battle against infectious diseases.