BackgroundSelf-medication is a worldwide issue that requires special attention due to the potentially harmful effects it can have not only on pregnant women but also on the fetus.ObjectivesThis study assessed the magnitude of self-medication practice and associated factors among pregnant women following antenatal care (ANC) in primary healthcare settings in the North Wollo Zone of Ethiopia.MethodsAn institutional-based cross-sectional study was conducted on 395 pregnant mothers who attended ANC follow-up in selected health centers in the North Wollo Zone of Ethiopia from April 20 to May 20, 2021. A multi-stage sampling method was employed to enroll participants. A face-to-face structured interview was conducted to collect the data. A logistic regression analysis was used to determine the factors associated with self-medication practice. Apvalue < 0.05 at the 95% confidence level was considered statistically significant.ResultsOut of a total of 444 participants approached, 395 (89%) participated in the study. Of these, 44.6% reported practicing self-medication during the current pregnancy. Age < 35 (AOR = 2.18, 95% CI 1.02–9.15;p= 0.032), rural residence (AOR = 3.01, 95% CI 1.43–10.19;p= 0.017), and previous medication use (AOR = 5.02, 95% CI 1.24–12.93;p= 0.015) were found to have a significant association with self-medication practice.ConclusionSelf-medication was highly prevalent among pregnant women in the study setting and result indicates need for critical action. Younger rural women with a history of self-medication use should be provided counselling to find a prescription medication, and measures are needed to minimize self-medication related harm in pregnant women.Supplementary InformationThe online version contains supplementary material available at 10.1186/s40545-023-00584-7.