Abstract <p>This review discusses the significance of 1,3,4-oxadiazole (OXD) derivatives in medicinal chemistry, focusing on their diverse biological activities and the importance of eco-friendly production methods. The primary objective is to explore green synthetic routes that minimize environmental impact while preserving the pharmacological potential of OXD derivatives. Traditional methods, which typically involve acid hydrazides and dehydrating agents like phosphorus oxychloride, often yield low amounts of product and generate hazardous byproducts, and are also addressed. In contrast, green chemistry techniques, such as solvent-free processes, microwave-assisted synthesis, and the use of non-toxic catalysts, have been shown to improve reaction efficiency, reduce energy consumption, and produce higher yields with fewer environmental risks. The review also emphasizes the structural flexibility of the 1,3,4-oxadiazole core moiety and its ability to be tailored into various derivatives with promising biological activities, including antibacterial, antitubercular, antifungal, anticancer, and antioxidant properties. Green synthetic approaches not only enhance the yield and purity of OXD derivatives but also improve their biological efficacy against cancers and drug-resistant bacteria. Future considerations are discussed, emphasizing the dual benefits of these approaches in supporting environmentally sustainable practices and enhancing the pharmacological profiles of OXD derivatives, which offer a promising strategy for the development of novel therapeutic agents in the pharmaceutical industry.</p>