Background: Self-medication is the act of consuming medicines at the individual's own suggestion or recommendation by a family member, a friend, or untrained or unqualified health care personnel. Practice of self-medication differs among individuals and is influenced by several factors like age, educational status, gender, family monthly income, level of knowledge, and non-chronic illness.Aim: This study aims to compare the prevalence, knowledge of impact, and practice of self-medication among adults in urban and rural communities.Materials and methods: A non-experimental comparative study was conducted among adults in urban and rural communities practicing self-medication. In this study, the target population is aged between 21 and 60 years. The sample size is 50 urban adults and 50 rural adults. A convenient sampling technique method was used. The prevalence was assessed through a survey questionnaire. The self-structured questionnaire was used to assess the knowledge of impact, and a non-observational checklist was used to assess the practice which was adopted by the research investigator.Results: The present study results showed that the majority had inadequate knowledge (88%) regarding consuming self-medication in rural adults, there was overuse of self-medication practice (64%) in rural adults, and there was moderate usage of self-medication practice (64%) in urban adults. There was a statistically significant difference between knowledge and practice regarding self-medication among adults in urban and rural communities which was highly significant at p<0.05.Conclusion: In the present study, comparison of the results of knowledge of impact and practice of self-medication among urban and rural adults revealed that urban adults have better adequate knowledge of impact of self-medication which helps them to practice moderate usage of self-medication.