Background There is a paucity of primary data to understand the overall pattern of disease and injuries as well as related health-service utilization in resource-poor countries in Africa. Objective To generate reliable and robust data describing the pattern of emergency presentations attributable to communicable disease (CD), non-communicable disease (NCD) and injuries in three different regions of Mozambique. Methods We undertook a pragmatic, prospective, multicentre surveillance study of individuals (all ages) presenting to the emergency departments of three hospitals in Southern (Maputo), Central (Beira) and Northern (Nampula) Mozambique. During 24-hour surveillance in the seasonally distinct months of April and October 2016/2017, we recorded data on 7,809 participants randomly selected from 39,124 emergency presentations to the three participating hospitals. Applying a pragmatic surveillance protocol, data were prospectively collected on the demography, clinical history, medical profile and treatment of study participants. Findings A total of 4,021 males and 3,788 (48.5%) females comprising 630 infants (8.1%), 2,070 children (26.5%), 1,009 adolescents (12.9%) and, 4,100 adults (52.5%) were studied. CD was the most common presentation (3,914 cases/50.1%) followed by NCD (1,963/25.1%) and injuries (1,932/24.7%). On an adjusted basis, CD was more prevalent in younger individuals (17.9±17.7 versus 26.6±19.2 years;p<0.001), females (51.7% versus 48.7%-OR 1.137, 95%CI 1.036-1.247;p = 0.007), the capital city of Maputo (59.6%) versus the more remote cities of Beira (42.8%-OR 0.532, 95%CI 0.476-0.594) and Nampula (45.8%-OR 0.538, 95%CI 0.480-0.603) and, during April (51.1% versus 49.3% for October-OR 1.142, 95% CI 1.041-1.253;p = 0.005). Conversely, NCD was progressively more prevalent in older individuals, females and in the regional city of Beira, whilst injuries were more prevalent in males (particularly adolescent/young men) and the northern city of Nampula. On a 24-hour basis, presentation patterns were unique to each hospital. Interpretation Applying highly pragmatic surveillance methods suited to the low-resource setting of Mozambique, these unique data provide critical insights into the differential pattern of CD, NCD and injury. Consequently, they highlight specific health priorities across different regions and seasons in Southern Africa.