<p>A number of existing studies on Mpox in Nigeria predominantly focused on urban centres and used quantitative methods, with limited attention to the role of culture in shaping disease perception and response in rural areas; this constitutes a research gap. Therefore, this qualitative study employed an in-depth interview approach to examine the cultural factors influencing the perceptions and responses of residents in Famia, a rural community in Osun State, Nigeria, in the context of the emerging Mpox outbreak. Purposive sampling was utilized to recruit a diverse sample of 25 participants with relevant experiences and perspectives. Reflexive thematic and content analysis techniques were used to analyze the collected data. The study found that various cultural factors influenced Mpox prevention, including religious beliefs, misperceptions, conspiracy theories, belief in efficiency of trado-medical practices, economic implications, cultural legacies, and the absence of an indigenous name for Mpox. The study concluded that findings highlighted the importance of holistic public health approaches that consider the interplay between cultural, socioeconomic, and environmental factors to improve health outcomes and reduce disease transmission.</p>