Background Low birth weight is the leading cause of infant and child mortality and contributes to several poor health outcomes. Proper knowledge of risk factors of low birth weight is important for identifying those mothers at risk and thereby for planning and taking appropriate actions. This study investigates factors predicting occurrence of low birth weight among deliveries at Debreberhan Referral Hospital. Methods Facility-based unmatched case-control study was conducted among deliveries that took place at Debreberhan Referral Hospital. Birth records and mothers' ANC files were reviewed from April to June 2016. The study participants were selected by consecutive sampling technique. Data analysis was performed by SPSS version 20. Binary logistic regression analysis was performed to identify predictors of low birth weight. Result A total of 147 birth records of babies with low birth weight (cases) and 294 birth records of babies with normal birth weight (controls) were reviewed. The birth weight of low birth weight babies (cases) ranged from 1000 grams to 2400 grams with median (±IQR) of 2200 grams (±300 grams), whereas it ranged from 2500 grams to 4500 grams with median (±IQR) of 3100 grams (±525 grams) among controls. Preterm birth (AOR = 5.32; CI = 2.959–9.567), history of any physical trauma experienced during pregnancy (AOR = 13.714; CI = 2.382–78.941), and history of any pregnancy complication (AOR = 2.708; CI = 1.634–4.487) were predictors of low birth weight. On the other hand, cesarean delivery (AOR = 0.415; CI = 0.183–0.941) and instrumental (AOR = 0.574; CI = 0.333–0.987) modes of delivery as well as maternal history of chronic diabetes (AOR = 0.275; CI = 0.090–0.836) had preventive effect of low birth weight. Conclusion Preterm birth, history of experiencing any physical trauma during pregnancy, and history of any pregnancy complication were predictors of low birth weight, whereas cesarean and instrumental delivery had positive effect to preventing low birth weight.