The clinical manifestation of COVID-19 evolved significantly throughout the pandemic, shifting from severe, often fatal pneumonia to a more manageable, multi-organ infection. This change reflects advancements in medical knowledge, improved treatments, and widespread vaccination efforts. However, the contribution of viral evolution, including reduced virulence to evade immunity and enhanced transmissibility, remains under investigation. This study utilizes the K18-hACE2 mouse model that replicates key features of human COVID-19, demonstrating a dose-dependent progression from asymptomatic or mild disease at lower viral doses to severe, lethal outcomes at higher doses. The study compares four representative SARS-CoV-2 variants to identify and characterize biomarkers of pathogenicity and host responses. Mice were infected intranasally with increasing doses of SARS-CoV-2, while sham-infected animals received PBS. Daily monitoring of weight loss and symptoms, along with Kaplan–Meier survival analysis, revealed significant weight loss correlating with poor survival. Following determination of the optimal viral dose, mice were sacrificed at various time points to evaluate disease progression. Viral load was highest in the lungs and brain. Lung pathology, assessed via immunohistochemistry, revealed intra-alveolar hemorrhages, edema, pneumocyte hyperplasia, congestion, inflammation, and multinucleated giant cells. Lipid inflammatory markers were analyzed on plasma samples collected at different time points. Of 58 markers analyzed, 50 were detectable in ≥50% of samples and subjected to statistical analysis, revealing significant shifts. Brain tissues from infected and control mice were analyzed for neurodegenerative markers. IFN-I/III gene expression in lung and spleen cells was assessed at four post-infection time points to investigate innate immune responses. This study provides a comprehensive analysis of SARS-CoV-2 variant pathogenicity and host responses using the K18-hACE2 mouse model. By elucidating the mechanisms of disease progression and immune response, these findings deepen our understanding of COVID-19 and its evolving clinical manifestations. Ongoing investigations aim to identify differences in innate immune responses among SARS-CoV-2 variants.