Background Development of drug resistance caused by self-medication with antibiotics, can be seen as one of the growing global threats. Self-medication is defined as the selection and use of medicines by individuals to treat self-recognized illnesses or symptoms. The purpose of this study is to assess the practice of self-medication with antibiotics and associated factors among the community of Asmara, Eritrea. Methods This was a community based descriptive cross-sectional study conducted in 16 selected sub-districts of Asmara from September to November 2017. A Two-stage cluster sampling was employed to select study sites and participants. Data was collected in a face to face interview with a structured questionnaire and entered to CSPro version 6.2. Descriptive statistics, cross-tabulation and logistic regression were executed using SPSS version 22. Results A total of 580 study participants were recruited with a response rate of 99.5% ( N = 577). The prevalence of Self-medication with antibiotics (SMA) in this study was found to be 45.1% [95% CI (40.5, 49.6)] and majority of them practiced once or twice in a period of 12 months. The main reasons for SMA were previous successful experience (34.4%) and the illness being ‘not serious enough to seek medical care’ (25.7%). Of those who self-medicated, 84.1% of used amoxicillin at least once. Wound infection (17.9%) and sore throat (13.9%) were the most self-recognized complaints that required self-medication. Antibiotics were supplied and recommended mostly by the community drug outlets. Only Sex ( p = 0.046), knowledge ( p = 0.019) and attitude ( p < 0.001) of the participants were found significantly associated with the practice of SMA in the multivariate logistic regression. Conclusions Though majority of the respondents considered self-medication with antibiotics as inappropriate practice, about half of them were practicing it anyway. Therefore immediate attention from relevant bodies is required. Electronic supplementary material The online version of this article (10.1186/s12889-019-7020-x) contains supplementary material, which is available to authorized users.