Background Preterm birth is one of a public health issue worldwide. It is a single most important cause of death in the first month of life and second leading cause of death in children aged less than five years. The cause of preterm birth is multifactorial and not well identified. Therefore, the aim of this study was to identify determinants of preterm birth in public hospitals of Horro Guduru Wallaga zone, Western Ethiopia. Methods Hospital-based unmatched case-control study design was carried out in public hospitals of Horro Guduru Wallaga zone which involved 78 cases and 155 controls. Data were collected using pre-tested questionnaires from three hospitals. Data were entered in to EpiData and exported to SPSS version 25 for analysis. Frequency and proportion were computed to summarize the data. Multivariable binary logistic regression analysis was used to determine the association of predictor and response variable at P < 0.05. Adjusted odds ratio with 95% CI was used to show the strength of association between predictors and outcome variables. Results Out of 233 mothers, 231 (78 cases and 153 controls) were participated with response rate, 99.14%. The result of this study showed that not attending ANC (AOR= 4.61, 95%CI; 1.54, 13.79), history of abortion(AOR =3.88, 95% CI; 1.62, 9.30), Premature rupture of the membrane (AOR=3.91,95% CI;1.15,13.25), Sexually transmitted illness (AOR=3.51,95% CI; 1.26,9.76) and physical violence (AOR=2.78, 95%CI;1.19,6.52) had significant association with preterm birth. Conclusions The result of this study showed that not attending antenatal care, history of abortion, premature rupture of membrane, sexually transmitted illness and physical violence identified as potential risk factors of preterm birth. Therefore, it is important to encourage pregnant mothers to have optimum antenatal care follow-up. Healthcare providers should also focus on screening and counseling pregnant mother on obstetric complications and limiting physical violence.