Background: Birth weight is one of the major determinants of perinatal survival, infant morbidity, and mortality. There are only few published reports on assessment of low birth weight in Ethiopia and the determinants of low birth weight have not been well characterized. Objective: The aim of this study was to assess determinants of low birth weight among live birth newborns delivered at public hospitals in Gamo Gofa Zone, South Ethiopia. Methods: Institution-based case control study was conducted from February 25 to April 25, 2018 and consecutively selected 60 cases and 240 controls were enrolled in this study. The data were collected using face-to-face interview and review of medical records. Moreover, we have measured the newborns’ birth weight using a standard weight scale and mother’s mid-upper arm circumference using a standard World Health Organization mid-upper arm circumference measuring tape. Statistical analysis of the data was done using SPSS version 21. Results: A total of 300 newborns were included in the study. Late antenatal care booking (adjusted odds ratio = 1.87, confidence interval = [1.32–2.6]), birth interval <2 years (adjusted odds ratio = 0.385, confidence interval = [0.176–0.83]), anemia (adjusted odds ratio = 4.4, confidence interval = [1.84–10.5]), mid-upper arm circumference <23 cm (adjusted odds ratio = 7.99, confidence interval = [3.5–20.3]), nutritional counseling (adjusted odds ratio = 5.85, confidence interval = [2.14–14.8]), and husband smoking (adjusted odds ratio = 4.73; confidence interval = [1.42–15.7]) were found to be determinant factors of low birth weight. Conclusion: Most of the determining factors of low birth weight were preventable. Therefore, clinical and public health interventions should target on those determinant factors to prevent its adverse effects.