Background: Insights into SARS-CoV-2 in Uganda were limited throughout the epidemic due to incomplete access to diagnostic testing and limited formal surveillance systems. From September 2021 to August 2022, we conducted a household-based surveillance study using both rapid antigen and serologic testing to determine the SARS-CoV-2 infection burden and seroprevalence among residents of South-Central Uganda. Methods: Household members in four communities within the districts of Kyotera and Lyantonde were recruited. Using a structured questionnaire, participants provided sociodemographic and other information. They also provided nasal swabs and blood samples. Swabs were tested using SD Biosensor Standard Q COVID-19 rapid antigen tests. Sera were tested for antibodies to SARS-CoV-2 using the VivaChek Biotech VivaDiag TM IgM/IgG rapid test. We assessed positivity rates overall and by selected socio-demographic characteristics. Modified Poisson regression was used to assess the relationships between IgG seropositivity and antigen positivity, while accounting for clustering by community. Results: From September 2021 to August 2022, 11,113 participants were enrolled. The mean age was 20.6 (SD = 16.1) years, with an average household size of 3.9 (SD = 2.6) persons. Among 11,086 persons tested for SARS-CoV-2 antigen, overall positivity was 0.61%. Among 9,663 participants tested for SARS-CoV-2 antibodies, 6,630 (69%) were IgG-positive. COVID-19 vaccination coverage was 33.4%, and vaccination was significantly associated with IgG seropositivity (aRR = 0.96; 95% CI: 0.94-0.98; p <0.001). Conclusion: We observed high SARS-CoV-2 antigen rapid testing acceptability, low antigen positivity, and moderate IgG seroprevalence in this setting, suggesting low concurrent transmission but significant prior natural infection.