Background. Polytrauma refers to multiple life-threatening injuries to more than 2 bodily regions with some significant physiologic derangement. It is a major cause of morbidity and mortality globally. This study aimed to evaluate the epidemiological profile of polytrauma and outline the distribution of extremity fractures among cases in Northern Ghana. Methods. A retrospective cross-sectional study was conducted at the Accident and Emergency Department of Tamale Teaching Hospital. Data were extracted using a data collection tool onto MS Excel, cleaned, and exported onto SPSS version 26 for analysis. Descriptive statistics was used to present data in tables and charts. Analysis of variance (ANOVA) was used to assess whether there was a significant difference in the mean ISS and mean length of stay of the direct causes of death. Results. About 186 out of 5413 attendants to the emergency department were polytrauma, period prevalence of 3.4%. The male-to-female ratio was 1.9 : 1. Young adults (21–40 years) contributed 64% of the participants. The mean age of participants was 32.9 ± 15.4 years, and the mean ISS was 40.6 ± 13.1. Road traffic accidents (68.8%) were the most common cause of polytrauma. The mortality was 33.0%. Traumatic brain injury (TBI) was the most common direct cause of mortality (54.1%). There was a significant mean difference (MD) in the length of stay between multiple organ failure (MOF) and TBI (MD = 3.169, 95% C.I. = 0.48–5.86) and between MOF and hemorrhage (MD = 6.212, 95% C.I. = 2.62–9.80). Most fractures were closed (75.3%) and affected the lower limbs (61.5%). Open reduction and internal fixation were the most common surgery for extremity fractures. Conclusion. We recommend a concerted multidisciplinary policy framework geared towards promoting road safety and reducing accidents in Ghana. We also recommend a tailored robust treatment algorithm for managing traumatic brain injury in our settings to reduce mortality thereof.