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Human noroviruses (HuNoVs) are a prominent cause of gastroenteritis, yet fundamental questions remain regarding epidemiology, diversity and immunity in sub-Saharan African children. We investigated HuNoV seroprevalence and genetic and sociodemographic risk factors in Ugandan children. We randomly screened 797 participants of a longitudinal birth cohort (EMaBS) in Entebbe, and 378 children from a cross-sectional survey of rural island communities in Lake Victoria (LaVISSWA), for antibodies against multiple HuNoV genotypes by ELISA. We used linear regression modelling to test for associations between HuNoV antibody levels and sociodemographic factors, and for associations with the known human susceptibility rs601338 FUT2 Secretor SNP and histo-blood group antigens (A/B/O). Of the EMaBS participants, 76·6% were seropositive by age 1, rising to 94·5% by age 2-years. Seroprevalence in 1-year-olds of the rural LaVISSWA survey was even higher (95%). In the birth cohort, 99% of seropositive 2-year-olds had responses to multiple HuNoV genotypes. We identified associations between secretor-status and genogroup GII antibody levels (GII.4 p=3.1x10-52), as well as ABO and GI (GI.2 p=2.1x10-12). HuNoVs are highly prevalent in Ugandan children, indicating a substantial burden of diarrhoea-associated morbidity with recurrent infections. Public health interventions, including vaccination, and increased surveillance are urgently needed.