(1) Background: Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has rapidly evolved into a pandemic affecting virtually every country in the world. We evaluated the demographic, clinical, laboratory, and all-cause mortality of moderate and severe COVID-19 patients admitted to a tertiary care hospital in Oman during the different COVID-19 waves and variant types. (2) Methods: A case-series retrospective study was carried out between 12 March 2020 and 30 June 2022. All adults over the age of 18 with laboratory-confirmed COVID-19 were enrolled. Analyses were performed using univariate and multivariate statistics. (3) Results: A total of 1462 confirmed cases enrolled with the mean age of the cohort was 55 ± 17 years with significant differences among the groups (p = 0.006). A total of 63% and 80% of the patients were males and citizens of Oman, respectively. Patients infected with the Alpha COVID-19 variant type were more likely to have acute respiratory distress syndrome (ARDS) (ppppp = 0.001) compared with other COVID-19 variant types. The Delta (adjusted odds ratio (aOR), 1.8; 95% confidence interval (CI): 1.22–2.66; p = 0.003) and Omicron (aOR, 1.88; 95% CI: 1.09–3.22; p = 0.022) COVID-19 variant types were associated with higher all-cause mortality when compared to the initial COVID-19 variant. Old age (aOR, 1.05; 95% CI: 1.04–1.06; pp = 0.04), ICU admission (aOR, 3.41; 95% CI: 2.16–5.39; pp = 0.004), and ARDS (aOR, 5.75; 95% CI: 3.69–8.98; pp = 0.012). (4) Conclusions: Alpha and Delta variants were associated with a longer hospital stay, need for intensive care, mechanical ventilation, and increased mortality. Old age, cardiac renal dysfunction were commonly associated with Omicron variants. Large-scale national studies to further assess the risk factors for mortality related to COVID-19 waves are warranted. View Full-Text ►▼ Show Figures This is an open access article distributed under the Creative Commons Attribution License which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.