Background The practice of self-medication during pregnancy is a global challenge that necessitates high attention as it poses a potential threat to the pregnant mother and fetus. However, little is known regarding self-medication practice and its contributors among pregnant women in our setting. Objective The main aim of this study was to investigate the practice of self-medication and its contributing factors among pregnant women Methodology A cross sectional study was conducted among pregnant women at antenatal care follow-up of Ayder comprehensive specialized hospital, Tigray, Ethiopia. Written informed consent was obtained from each participant before interview. Simple random sampling technique was employed to recruit participants in to the study. Data were collected by interviewing participants using the structured questionnaire. Binary logistic regressions analysis was performed to determine the contributing factors of self-medication practice during pregnancy. A p value of less than 0.05 was considered as significant. Results A total of 250 pregnant women were included in the study. Of the total, 40.8% practiced self-medication during the current pregnancy. Morning sickness (39.2%), headache (34.3%), and upper respiratory tract infections (29.4%) were the leading indications for self-medication. According to participant report, ease of access to medicines (25.5%), feelings that the disease is minor (21.6%) and timesaving (19.6%) were the most commonly reported reasons for self-medication practice. Absence of health insurance (AOR: 2.75, 95%CI: 1.29–5.89) and being on first trimester of pregnancy (AOR: 2.44, 95%CI: 1.02–5.86) were significant contributors of self-medication practice among pregnant women. Conclusion In our study, high prevalence of self-medication was reported among pregnant women. Self-medication practice during pregnancy was higher among pregnant women on first trimester and those who were not having health insurance. Therefore, intervention programs should be designed to minimize the practice of self-medication during pregnancy.