Background Surveillance of COVID-19/SARS-CoV-2 dynamics is crucial to understanding natural history and providing insights into the population’s exposure risk and specific susceptibilities. This study investigated the seroprevalence of SARS-CoV-2 antibodies, its predictors, and immunological status among unvaccinated patients in Cameroon. Materials and Methods A multicentre cross-sectional study was conducted between January and September 2022 in the town of Douala. Patients were consecutively recruited, and data of interest were collected using a questionnaire. Blood samples were collected to determine Immunoglobin titres (IgM and IgG) by ALFA, CD4+ cells by flow cytometry, and interferon gamma (IFN- γ) and interleukin-6 (IL-6) by ELISA. Results A total of 342 patients aged 41.5 ± 13.9 years were included. Most participants (75.8%) were asymptomatic. The overall prevalence of IgM and IgG was 49.1% and 88.9%, respectively. Ageusia and anosmia have displayed the highest positive predictive values (90.9% and 82.4%) and specificity (98.9% and 98.3%). The predictors of IgM seropositivity were being aged 60 – 70 years (aOR = 0.54, p = 0.02) and ageusia (aOR = 9.31, p = 0.01), whereas those of IgG seropositivity included health facility (aOR = 0.23, p = 0.02) and ageusia (aOR = 0.21, p = 0.04). CD4+, IFN-γ, and IL-6 were impaired in seropositive individuals, with a confounding role of socio-demographic factors or comorbidities. Conclusion Although the WHO declared the end of COVID-19 as a public health emergency, the findings of this study indicate the need for continuous surveillance to adequately control the disease in Cameroon.