This prospective cohort study assessed clinical, laboratory, and virological factors associated with mortality in 227 ICU patients with RT-qPCR-confirmed SARS-CoV-2 infection (September 2020–March 2021). Data were extracted from medical records, viral load was measured by RT-qPCR cycle threshold (Ct), and outcomes were compared. Survival was analyzed using the Kaplan–Meier curves. Non-survivors were significantly older ( p < 0.001) and more likely to have hypertension ( p = 0.014), chronic respiratory disease ( p = 0.042), and tobacco exposure ( p = 0.003). At admission, non-survivors had higher leukocyte counts ( p = 0.001), D-dimer ( p = 0.028), and creatinine levels ( p = 0.001), as well as lower arterial pH ( p = 0.006). Tracheal intubation was significantly more frequent in this group ( p < 0.001). During hospitalization, non-survivors presented persistently elevated leukocyte counts and more complications, including acute kidney injury, septic shock, and cardiac arrest ( p < 0.001). They also had longer hospital stays ( p = 0.046). Viral load was higher in non-survivors ( p = 0.026) and among those requiring intubation ( p = 0.042) and with cardiovascular disease ( p = 0.016). Survival analysis showed reduced survival among patients aged ≥65 years ( p = 0.004), with chronic respiratory disease ( p = 0.029), or with tobacco exposure ( p = 0.028). These findings highlight the impact of age, comorbidities, and viral load on COVID-19 severity and mortality, providing insights for clinical management and risk stratification.