(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) (p < 0.001), stay longer in the hospital (p < 0.001), and get admitted to the intensive care unit (ICU) (p < 0.001). At the same time, those who had the Omicron COVID-19 type were more likely to have renal impairment (p < 0.001) and less likely to be associated with non-invasive ventilation (NIV) (p = 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; p < 0.001), the presence of respiratory disease (aOR, 1.58; 95% CI: 1.02–2.44; p = 0.04), ICU admission (aOR, 3.41; 95% CI: 2.16–5.39; p < 0.001), lower eGFR (aOR, 1.61; 95% CI: 1.17–2.23; p = 0.004), and ARDS (aOR, 5.75; 95% CI: 3.69–8.98; p < 0.001) were also associated with higher mortality while NIV requirements were associated with lower odds of dying (aOR, 0.65; 95% CI: 0.46–0.91; p = 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.

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