Introduction: The global COVID-19 pandemic has disproportionately impacted people with weakened immune systems. Non-communicable diseases, which include diabetes and cancer, are the top causes of weakened immune systems, recording up to 74% of all deaths globally. Studying the seroprevalence is crucial in understanding the epidemiology of the virus and contributes to the improved management of COVID-19 amongst patients with cancer and diabetes. Methods: The study was a single-center prospective study that tested serum samples for routine chemical analysis from March to July 2022 at NHLS, Chemical Pathology, Polokwane laboratory using the COVID-19 IgG/IgM Rapid Test Cassette -Orient Gene Biotech, Zhejiang, China. The assay tests antibodies against SARS-CoV-2 in the early (lgM) and later stage (lgG) of infection. Results: Of the 207 patients with diabetes, 84% had detectable IgG and IgM antibodies against SARS-CoV-2. Similarly, 81% of the 283 cancer patients had detectable IgG and IgM antibodies against SARS-CoV-2. The patients with diabetes had a median age of 56 years (range: 0-91), and 60% were females. The cancer patients had a median age of 62 years (range: 49-72), and 40% were females. Conclusion: The study demonstrates a high SARS-CoV-2 IgG and IgM antibody seroprevalence in diabetic and oncology patients at Pietersburg Hospital, Limpopo, South Africa. These findings emphasize the importance of ongoing serologic testing to track the pandemic, particularly among immunocompromised patients, and inform the development of effective public health strategies to mitigate COVID-19 transmission.