The emergence of COVID-19 underscored the urgent need for fast and reliable diagnostic methods for SARS-CoV-2 detection. The Xpert® Xpress SARS-CoV-2 assay, a rapid RT-PCR-based platform, was introduced as a potential solution for timely diagnosis. This study assessed its diagnostic performance among hospitalized patients during the first wave of the pandemic in India. A total of 1190 patients admitted with suspected COVID-19 and presenting acute hypoxic respiratory symptoms were included in this cross-sectional analysis. Nasopharyngeal swabs were processed using the Xpert® assay. Additionally, a randomly selected subgroup of 100 samples was retested using the TaqPath™ COVID-19 Combo Kit to evaluate concordance. Statistical analysis involved the use of GraphPad Prism and MedCalc, employing Fisher’s exact test and ROC curve analysis to assess test performance. The study cohort had a mean age of 41.3 years, with males comprising 58.5%. Notably, individuals aged 45 years and above showed the highest infection rates. The Xpert® assay demonstrated perfect sensitivity and negative predictive value (NPV), accurately identifying positive cases while effectively ruling out negatives. These findings suggest that the Xpert® Xpress assay is a valuable rapid diagnostic tool for SARS-CoV-2, exhibiting high diagnostic precision. Further prospective studies with expanded cohorts are recommended to validate its broader clinical utility.