Low levels of living standards amongst street dwellers worldwide limit their access to conventional healthcare services, resulting in self-medication use for the treatment of an illness. Nevertheless, self-medication use has risks, including adverse drug reactions, increased polypharmacy, drug resistance, drug dependence, drug interactions and incorrect diagnosis. Ethiopia has a large street-dwelling community; however, there are no studies conducted in Ethiopia assessing self-medication use amongst street dwellers. This study provides insight into self-medication use and predictors amongst street dwellers in Ethiopia. A community-based, multicentre cross- sectional study was conducted amongst street dwellers from 1 September 2022 to 1 February 2023 at community drug-retail outlets in the three major cities in the Amhara region of Ethiopia. The data were obtained using an interviewer-administered questionnaire. Frequencies and percentages of descriptive statistics were calculated. Bivariable and multivariable logistic regression analyses were employed to indicate predictors of self-medication use. To determine statistical significance, a 95% confidence interval with a p value below 0.05 was utilized. The prevalence of self-medication use was 67.4%. Time and financial savings were reported as the reasons for most self-medication use. The most commonly reported illnesses for which people sought self-medication were gastrointestinal diseases. Low monthly income (adjusted OR 3.72, 95% CI 2.34-5.91) and residing near sewage areas (adjusted OR 3.37, 95% CI 2.03-5.58) were significantly associated with self-medication use. Street dwellers had a high rate of self- medication use. Residing near sewage areas and having a low level of income were factors in self-medication use. Gastrointestinal diseases, respiratory ailments and dermatological conditions were the most frequently reported complaints, whereas antimicrobials and anthelmintics were the most commonly used medications. We recommend that healthcare services enhance outreach programmes to the most vulnerable people, such as street dwellers, especially those with lower monthly incomes and who live near sewage areas, to reduce self-medication rates.