Background: Since the beginning of the SARS-CoV-2 pandemic, the ability to predict the trajectory of the disease has represented a major challenge for clinicians. There is recent evidence that complete blood cell count (CBC)-derived inflammation indexes have predictive value in COVID-19. We aimed to describe any changes in the clinical features, CBC-derived ratios, and outcomes of patients admitted to our hospital across two temporally distinct waves. Methods: We retrospectively assessed and compared the clinical characteristics and blood cell count values of patients hospitalized during the second and fourth waves of COVID-19, and explored any outcome differences in terms of the level of respiratory support required and transfer to intensive care. Results: We observed that fourth-wave patients were older, less male-predominant, and carried more comorbidities compared to the second-wave patients but, nevertheless, experienced more favorable outcomes. A strong internal correlation was documented for both waves between outcomes and CBC-derived ratios, with the fourth-wave cases displaying lower admission values of the neutrophil-to-lymphocyte ratio (NLR), derived NLR (dNLR), platelet-to-lymphocyte ratio (PLR), and systemic inflammation index (SII). No significant differences were found for lymphocyte-to-monocyte ratio (LMR), systemic inflammation response index (SIRI), and aggregate index of systemic inflammation (AISI). Conclusions: We observed that both admission values of CBC-derived indexes and adverse respiratory outcomes decreased from the second to the fourth wave of COVID-19. These data represent a contribution to the existing knowledge on the role of CBC-derived indexes as a potential tool to help clinicians to quickly differentiate in-hospital patients at increased risk of serious illness and death.