In low-income countries, complex comorbidities and weak health systems confound disease diagnosis and treatment. Yet, data-driven approaches have not been applied to develop better diagnostic strategies or to tailor treatment delivery for individuals within rural poor communities. We observed symptoms/diseases reported within three months by 16 357 individuals aged 1+ years in 17 villages of Mayuge District, Uganda. Symptoms were mapped to the Human Phenotype Ontology. Comorbidity networks were constructed. An edge between two symptoms/diseases was generated if the relative risk greater than 1, ϕ correlation greater than 0, and local false discovery rate less than 0.05. We studied how network structure and flagship symptom profiles varied against biosocial factors. 88.05% of individuals (14 402/16 357) reported at least one symptom/disease. Young children and individuals in worse-off households-low socioeconomic status, poor water, sanitation, and hygiene, and poor medical care-had dense network structures with the highest comorbidity burden and/or were conducive to the onset of new comorbidities from existing flagship symptoms, such as fever. Flagship symptom profiles for fever revealed self-misdiagnoses of fever as malaria and sexually transmitted infections as a potentially missed cause of fever in individuals of reproductive age. Network analysis may inform the development of new diagnostic and treatment strategies for flagship symptoms used to characterize syndromes/diseases of global concern.