Abstract Background: Coronavirus disease 2019 (COVID-19) continues to be a significant global public health issue. Aims and Objectives: This study aims to describe the demographic characteristics, comorbidities, clinical presentations, inflammatory biomarkers, and chest computed tomography (CT) findings of patients with severe acute respiratory infection (SARI) at a tertiary care hospital in Odisha, India. Additionally, the study aims to evaluate different COVID-19 diagnostic methods. Materials and Methods: A prospective observational study was conducted at a tertiary care hospital in Odisha, India. All admitted SARI patients underwent COVID-19 testing. Data on demographics, clinical presentations, laboratory investigations, and outcomes at 72 h were collected. COVID-19 diagnostic methods were also analyzed. Statistical Analysis: The statistical analysis was performed using GraphPad Prism 9.5. Results: Among the 830 patients studied, 305 tested positive for COVID-19. The rapid antigen test (RAT) demonstrated a sensitivity of 93.85% and a specificity of 97.43% compared to the real-time reverse transcriptase-polymerase chain reaction (RT-PCR) test. Discrepancies with RAT results were noted in cases with higher cycle threshold (Ct) values (>25). A male predominance was observed, with a mean age of 43.30 ± 15.19 years in the COVID-19-positive group and 40.95 ± 17.15 years in the COVID-19-negative group. Patients with multiple comorbidities (15.68%) had a higher susceptibility to COVID-19 infection. The COVID-19-positive group showed a significantly elevated neutrophil-to-lymphocyte ratio (NLR) (P = 0.0001) and thrombocytopenia (P = 0.001). Inflammatory biomarkers, including CRP, LDH, ferritin, D-dimer, and IL-6, were markedly elevated in swab-positive cases. Bilateral chest involvement and ground glass opacities were common radiological findings in both groups. Conclusion: In resource-limited settings, the RAT is considered an alternative screening tool for COVID-19. Initial laboratory and radiological investigations may aid clinicians in effective management of such patients.