Background Macrosomia is defined as a birth weight of newborns ≥4000 grams irrespective of gestational age. It is becoming a burning public health issue in most developing countries and contributes to maternal and newborn complications. Though macrosomia has been increasing in Ethiopia, evidence about its magnitude and associated factors is limited yet. Therefore, this study aimed to assess the prevalence and associated factors of macrosomia among newborns delivered at the University of Gondar Comprehensive Specialized Hospital, Northwest Ethiopia. Methods An institution-based cross-sectional study was carried out from February 23rd to April 23rd, 2020. A total of 491 mothers and their newborns were included in the study. The data were collected by interviewing the mothers and reviewing their charts using a structured questionnaire. The outcome variable was newborn birth weight. Data were entered using Epi-data version 4.6 and analyzed using STATA version 14 software. Bivariable and multivariable binary logistic regression were used to identify the factors associated with macrosomia. Results The prevalence of macrosomia was 7.54%. Gestational age ≥40 weeks (adjusted odds ratio (AOR) = 4.1 (95% CI = 1.7–9.7)), diabetes mellitus (AOR=5.5 (95% CI = 1.2–25)), previous history of macrosomia (AOR = 3.7 (95% CI = 1.4–10)), and male sex (AOR = 3.4 (95% CI = 1.3–8.7)) were significantly associated with macrosomia. Conclusion In the current study, the prevalence of macrosomia was relatively high. The study revealed that maternal diabetes mellitus, higher gestational age, history of macrosomia, and male newborns were the predictors of macrosomia. Thus, obstetric caregivers should give attention to early detection and management of mothers with diabetes mellitus, history of macrosomia, and gestational age of ≥40 weeks during pregnancy to prevent macrosomia and its complications.