The different strains of SARS-CoV-2 were detected and labeled in 2021. Each strain differs in both clinical symptoms and severity. Previous studies found different clinical symptoms and treatment outcomes between outbreak waves; however, data in Southeast Asia were limited. This study collected data of hospitalized COVID-19 patients from a Tertiary hospital in Thailand between January 2020 and December 2023 and analyzed patients’ data in each outbreak wave using Pearson’s chi-square. A total of 1084 inpatients were included for analysis. The median age was 64 (IQR, 0.4–100) years. The patients were hospitalized in predominantly Alpha (22.78%), Delta (21.68%), and Omicron (5.07%) periods of the virus outbreak. The largest age group was elderly (over 65 years old) in all three variant of concern (VOC) periods; 82.65% of the patients had comorbidities, including 58.5% hypertension, 46.5% dyslipidemia, and 42.0% diabetes mellitus (DM). The study found pneumonia at 67.53%, septic shock at 4.61%, acute respiratory distress syndrome (ARDS) at 2.86%, and congestive heart failure at 0.83% in all age groups with no significant difference between outbreak periods. The overall mortality rate was 16.14%. A total of 75% of deaths occurred in patients over 65 years old. The mortality rates in each VOC period were 20.0% Delta, 19.83% Alpha, and 13.23% Omicron. In the elderly group, the mortality rates were Delta 15.32%, Alpha 11.75%, and Omicron 10.88%. The Omicron VOC was less severe than other variants, particularly in the elderly (65 years). There were no significant differences in the younger (<65 years) age group. The elderly still had more severe symptoms and the highest mortality rates in every wave of outbreak.