BACKGROUND: Globally, 75,000 maternal deaths occur each year from puerperal sepsis, with higher rates in low-income countries. In Ethiopia, puerperal sepsis is the fourth leading cause of maternal morbidity and mortality. This study aimed to identify determinants of puerperal sepsis among postpartum women admitted to public hospitals in Harar, eastern Ethiopia. METHOD: A retrospective unmatched case-control study was conducted from June 15 to July 15, 2022, among 423 postpartum women (106 cases and 317 controls) in Public Hospitals in Harar town, Harari Regional State, Eastern Ethiopia. Participants were selected using a simple random sampling method based on medical registration numbers. Data was extracted using a checklist and analyzed using SPSS version 25 statistical software. Logistic regression was used to identify determinants of puerperal sepsis, with adjusted odds ratios and a 95% confidence interval to estimate the strength and direction of the association. Statistical significance was declared at a p-value of less than 0.05. RESULTS: The determinants of puerperal sepsis were found to be cesarean section delivery (AOR = 2.32, 95% CI 1.24-4.33), rupture of membranes lasting more than 24 h (AOR = 4.34, 95% CI 1.93-9.76), labor duration exceeding 24 h (AOR = 2.91, 95% CI 1.11-7.62), undergoing more than 4 vaginal examinations (AOR = 3.02, 95% CI 1.32-6.92), and being referred from other health institutions (AOR = 2.48, 95% CI 1.42-4.36). CONCLUSIONS: This study identified factors that independently predict puerperal sepsis, including mode of delivery, duration of labor, duration of rupture of the membrane, number of vaginal examinations, and referral status. It is essential for all stakeholders to work together to reduce the risk factors of puerperal sepsis.