Introduction: Substance use during the perinatal period is a significant public health concern, as it can have potential adverse effects on maternal and neonatal health outcomes. Unexpectedly, no previous studies have been conducted to assess the prevalence of substance use during the perinatal period among Ethiopian women. Therefore, this study aimed to determine the magnitude of substance use and its determinant factors during the perinatal period.Method: We conducted a hospital-based descriptive cross-sectional study among a systematically selected sample of 418 women who attended perinatal care between May and July 2022. Data were collected using an interviewer-administered structured questionnaire. Multivariate logistic regression analysis, with a 95% confidence interval and p-values less than 0.05, was employed to identify factors associated with substance use behavior.Result: The prevalence of perinatal substance use was found to be 38.3% (95% CI: 33.5–43.5). Of the women who used substances, 109 (26.1%) reported using chat, 46 (11.0%) reported alcohol consumption, and 5 (1.20%) reported using shisha. Factors significantly associated with substance use behavior during the perinatal period included a history of obstetric complications (AOR = 1.722, 95% CI: 1.022–2.902), the presence of chronic medical conditions (AOR = 3.784, 95% CI: 2.164–6.615), experiencing physical abuse (AOR = 5.323, 95% CI: 2.171–13.050), depression (AOR = 1.963, 95% CI: 1.028–3.749), and experiencing sleep disturbances (AOR = 2.016, 95% CI: 0.975–4.168). Conversely, giving birth to a live baby was found to be a protective factor against substance use behavior (AOR = 0.389, 95% CI: 0.187–0.810).Discussion: This study highlights a high prevalence of substance abuse among women during the perinatal period. In light of these findings, a comprehensive approach is recommended to address perinatal substance use among Ethiopian women. This should include the integration of preventive educational programs into perinatal care.