Truffle, an ascomycetous, hypogeous macrofungi, has long been recognized and valued for its therapeutic and dietary properties. Of late, a range of medicinal compounds, such as ergosterol, tuberoside anandamide, polysaccharides, and phenolics exhibiting anti-inflammatory, immunomodulatory, anticancer, antibacterial, and aphrodisiac properties have been identified in truffles. This review provides an update on contemporary truffle research with a focus on antimicrobial potentials and aims to draw the attention of researchers to exploit the therapeutic potential of truffles in the management of eye infections. The scholarly literature pertaining to the utilization of desert truffles in the management of ocular infections was systematically summarized and reviewed from multiple databases, including Scopus, Web of Science Core Collection, PubMed, and others. The essence of truffle is used as a remedy for trachoma and as an antiinflammatory agent for ocular problems. The most probable inhibitory constituents are the fungal lectins, polysaccharides, and laccases. Truffle lectins possess the ability to identify and remove bacterial exopolysaccharides. In addition, the fungal polysaccharides affect the bacterial defensive systems. Conversely, laccases facilitate the process of oxidizing phenols, resulting in the release of superoxide anion radicals and the production of hydrogen peroxide. The application of desert truffles in addressing ocular issues has been clinically observed to be satisfactory. The existing literature clearly indicates a pressing need for further investigation into the translation of the antimicrobial properties of crude truffle extract into truffle-based pharmaceutical formulations for clinical application.