Background: The coronavirus disease 2019 is highly infectious and patients with coronavirus diseases demonstrated a series of clinical symptoms caused by severe acute respiratory syndrome coronavirus-2. Without a break of the wave’s hematological profile of the patients is still ambiguous and differs from wave to wave. Objective: This study aimed to assess the hematological profile among coronavirus disease 2019 patients during the first and the second waves in Ethiopia. Methods: A multi-centered facility-based retrospective cohort study design was conducted at six coronavirus disease 2019 treatment centers. A total of 538 study participants were enrolled in the selected coronavirus disease 2019 treatment centers during the first and second waves of the pandemic. The demographic characteristics, underlying diseases, symptoms, and hematological parameters of patients were recorded. Data were entered into Epi-Data Manager 4.6 and analyzed using STATA 14.2. An independent sample t-test was used to assess the mean differences in hematological parameters across waves. Associations between categorical variables across waves were also determined using Chi-square and Fisher exact tests. Results: Among the total study participants, 240 (44.6%) and 298 (55.4%) patients were taken from wave-1 and wave-2, respectively. The average age of the study participants was 56.44 ± 16.25 years. The most frequent comorbidities in this study were hypertension, diabetes mellitus, ischemic heart disease, and asthma. The most presenting symptoms of COVID-19 infection across the two waves were presented. In the first wave, dry cough 166 (69.2%), fatigue 153 (63.75%), shortness of breath 148 (61.67%), and fever accounted 116 (48.33%), while during the second wave, dry cough 242 (81.2%), fatigue 244 (81.88%) shortness of breath 204 (68.47%) and fever account 180 (60.40%). White blood cells (WBC), neutrophils, and lymphocytes had shown increment during the first wave. Platelet count and platelet distribution width ( p < 0.001) had significant mean differences across the two waves, while the other had no significant mean difference. Conclusion: In the present study, dry cough, fatigue, shortness of breath, and fever were found to be the most presenting symptoms of COVID-19 infection across the two waves. Only the platelet count and platelet distribution width had significant mean differences across the two waves, while the other had no significant mean difference across waves.