BACKGROUND: Recent advancements in the synthesis of novel heterocyclic compounds, particularly oxadiazole derivatives, have garnered significant interest due to their broad pharmacological activities. Despite the oxadiazole ring being a relatively small structure, its derivatives have shown considerable therapeutic potential across a range of diseases. These compounds have been explored for a variety of biological effects, including anti-inflammatory, anticonvulsant, hypoglycemic, antitubercular, anxiolytic, antimicrobial, antitumor, and anticancer properties. The growing issue of drug resistance has further fueled research into the therapeutic promise of oxadiazolebased compounds, particularly for their ability to target resistant diseases. OBJECTIVE: This review aims to highlight the pharmacological profiles of oxadiazole derivatives, with a focus on how structural modifications can enhance their activity against specific therapeutic targets. Additionally, the review seeks to explore strategies for overcoming resistance mechanisms associated with these compounds, underscoring their potential in addressing emerging drugresistant diseases. CONCLUSION: Oxadiazole derivatives represent a promising class of compounds with significant therapeutic potential, particularly in the face of increasing drug resistance. Their diverse pharmacological activities and ability to be structurally optimized for specific therapeutic targets position them as valuable candidates for further research. Continued exploration of oxadiazole derivatives, with an emphasis on overcoming resistance, may lead to the development of novel treatments for a variety of challenging diseases.