Background In developing countries like Bangladesh, self-medication has become a predicament associated with health risks and clinical complications. To date, no studies have been conducted on the practice of self-medication among the indigenous population living in Chittagong Hill Tract (CHT). Objectives This study was aimed to determine the prevalence of self-medication and analyzing the factors associated with it among the indigenous population in CHT. Methods This cross-sectional study was conducted from late October to early December 2020; among different indigenous group populations residing in the three districts of CHT aged 18 or more. A pre-tested and semi-structured questionnaire was developed to collect data on socio-demographic characteristics, health status, frequency of self-medication, reasons for self-medication in last one year, as well as other variables. Multivariate logistic regression was performed to assess associated factors with self-medication. Results A total of 1350 people from different indigenous populations were interviewed, among whom 49.9% practiced self-medication. The rate of self-prescribed antibiotics usage (80.9%) was significantly higher compared to other drugs. Self-prescribed medications were mostly used for diarrhea and food poisoning (60.6%), cough, cold and fever (51.4%), and headache (51.4%). A common source of self-prescribed medicines was community or retail pharmacy and the most reported reason for self-prescribed medication was the long-distance of healthcare facilities from home. Conclusion The prevalence of self-medication is substantially high among indigenous people and the effect is alarming. Particular concern is the misuse of antibiotics and analgesic drugs. Increasing awareness among the population of the negative effect of self-medication and implementation of proper policies and actions are urgently needed to prevent self-medication among indigenous population in Bangladesh.