Abstract: Introduction This study assessed the causes of under-five (U5) deaths and examined the associated risk factors in northern Ghana. Methodology The study analyzed prospectively collected longitudinal data of children born between 1st January 2007 and 31st December 2012 and resident in the Navrongo Health and Demographic Surveillance System (NHDSS) in northern Ghana. Results Data from 20,651 children were analyzed with 1,056 under-five deaths and 51,783 person-years of observation. The overall mortality rate was 19.5 person-year of observation. The main cause of under-five deaths were malaria (19.5%). Being male (Hazards ratio [95% CI]; 1.20 [1.06 - 1.36]; p=0.004), children born to single mothers (1.3 [1.18 - 1.59]; p<0.001) and home deliveries (1.29 [1.12 - 1.48]; p<0.001) were associated with increased risk of mortality while children born to women aged 20-34 years (0.81 [0.67 – 0.98]; p=0.0.25) compared to those 19 years and below and those from high socioeconomic households (0.87 [0.74 - 1.03]; p=0.001) were associated with relatively lower risk of death. Conclusion Malaria remain the leading cause of under-five deaths in the study area. Adherence to prevailing malaria prevention measures including use of insecticide treated bed-nets, seasonal chemo-prophylaxis, indoor-residual spraying and adequate access to healthcare will greatly improve child survival.