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Abstract Background The World Health Organization (WHO) defines self-medication as taking medicine by someone to treat a health problem on their own, without a professional or doctor consultation. Self-medication is a growing public health concern globally, including in Afghanistan. This study aims to assess the prevalence of self-medication and its associated factors among the residents of Kandahar city. Methodology An analytical cross-sectional study was conducted in 12 districts of Kandahar city. A total of 401 adults were randomly selected and interviewed at private pharmacies using a structured questionnaire. Data collection was done from June 22 to July 17, 2025. The data was analyzed using SPSS version 26, with descriptive and analytical analyses, considering a p -value below 0.05 as statistically significant. Results A high prevalence (71.1%) of self-medication was observed among the residents of Kandahar. More than one type of medication was used by 47.1% participants, with paracetamol being the second most commonly used (18%). More than half (54.1%) of medicines were used for multiple symptoms. The specific reasons for self-medication were high doctor fees (18.5%) and previous experience with similar symptoms (13.7%). Pharmacies were identified as the primary source of self-medication (69.8%). Statistically significant factors associated with self-medication were found to be lack of awareness about self-medication ( p -value = 0.003), easy access to pharmacies ( p -value = <0.001), and the presence of symptoms ( p -value = <0.001). Conclusion Self-medication was highly prevalent in Kandahar, with key associated factors such as lack of awareness, easy access to pharmacies, and the presence of symptoms. It is recommended to implement health education programs to increase awareness about the adverse effects of self-medication. Strict implication of rules and regulations is required to control the sales of medicines without prescription in pharmacies.