Background: Self-medication is a common practice of using medicines without a medical supervision by the people themselves. Self-medication is likely to happen when people feel unwell, it is worse in the population with poor health seeking behavior. Therefore, it is important to assess the prevalence and factors associated with self-medication with antibiotics among the primary health care population in Madina city, Saudia Arabia. Methods: A cross sectional study was conducted from August to September 2019. The study population included two MOH primary health care centers. The population above 18 years old attended the selected primary health care centers was eligible to participate in the study. A self-filled questionnaire was used for data collection and data analyzed using the SPSS version 16 and association was tested using chi square. Results: Out 374 participants enrolled 187 from each MOH primary health care center, 126 were female and 248 were male with age ranging from 19 to 35 years with mean age of 23.91 years. The prevalence of self-medication with antibiotics was 57% and the most common used antibiotics was amoxicillin with prevalence of 32.08%. The common reported symptoms/diseases were headache (31.02%) followed by malaria and coughing with prevalence of 15.24% and 10.96% respectively. The commonest reasons of self-medication reported to be emergency illness (38.77%) and delaying of hospital services (24.33%). The commonest effects reported among respondents which practiced self-medication with antibiotics were worsening of the condition that they were suffering in (4.55%) and body rashes (2.67). There was no significant difference between self-medication practices among medical and non-medical participants (p = 0.676) Conclusion: The prevalence of self-medication with antibiotics was high among participants and there is no significant difference in both medical and non-medical participants. The most feared outcome on self-medication with antibiotics is antibiotic drug resistance which leads to treatment failure along with high financial costs and increase mortality rate following microbial infections.