Objective Macrosomia is associated with the risk of mortality and morbidity in neonates and their mothers. Despite the considerable public health effect of macrosomia, evidence on the determinants of macrosomia is limited in Northwest Ethiopia in general and in Amhara region in particular. Therefore, this study aimed to identify determinants of macrosomia among newborns delivered in referral hospitals in 2020 in Amhara region, Northwest Ethiopia. Methods A facility-based unmatched case-control study was conducted among 279 mothers and their newborns in Amhara region referral hospitals. Newborns weighing 4000 g and above and between 2500 and 3999 g were considered cases and controls, respectively. Bivariable and multivariable binary logistic regression were used to identify the determinants of macrosomia. Results In total, 273 of 279 mothers and their newborns (97.8% response rate) were included. The mean birth weights of cases and controls were 4312.97 ± 357.53 g and 3161.92 ± 452.12 g, respectively. Weight gain over pregnancy, antenatal follow up, physical activity during pregnancy, and neonate sex were the main determinants of macrosomia. Conclusion The main determinants of macrosomia were determined in this study. Government should place special emphasis on reducing the modifiable factors of macrosomia.