Mycetoma presents numerous therapeutic challenges, particularly due to delays in diagnosis, the toxic nature of existing antifungals and antibiotics treatments, and the lack of robust clinical evidence to guide care. This neglected tropical disease, which primarily affects low-resource regions, is further complicated by socio-economic barriers that limit access to healthcare and treatment. These challenges underscore the urgent need for better treatment options, more comprehensive research, and strengthened pharmacovigilance systems to monitor treatment safety and efficacy. Pharmacovigilance plays a critical role in managing mycetoma due to the prolonged and often toxic treatment regimens required. Adverse drug reactions, drug interactions, and treatment side effects need continuous monitoring to ensure patient safety. Effective pharmacovigilance systems should be adapted to the resource-limited settings where mycetoma is most prevalent, integrating into broader public health efforts to improve both the safety and efficacy of treatments. Such systems could greatly enhance patient outcomes by preventing unnecessary harm from toxic therapies and ensuring proper drug use. However, several barriers remain in endemic regions, including inadequate healthcare infrastructure, a lack of trained healthcare professionals, and limited access to pharmacovigilance tools. Addressing these issues requires building stronger national systems, offering more training for healthcare workers, and leveraging innovative technologies such as mobile health tools. Additionally, involving patients in reporting adverse effects could enhance the accuracy and reliability of pharmacovigilance data. Global collaboration and increased clinical research are also essential in improving mycetoma treatment. Investment in these areas, alongside the development of infrastructure and education in endemic countries, will help ensure safer long-term medical therapies and better outcomes for mycetoma patients. Furthermore, improving pharmacovigilance practices is critical to ensuring that vulnerable populations receive the most effective and safe care possible for this neglected disease.