Introduction: High-risk patients with COVID-19 benefit from early treatment to prevent severe outcomes. Sotrovimab, a monoclonal antibody, and oral antivirals such as nirmatrelvir/ritonavir and molnupiravir have been used for early intervention, but their comparative efficacy and safety, particularly during the Omicron-dominant phase, require further evaluation. Methods: A multicenter, retrospective study performed in southern Italy including all adult patients who received early antiviral treatment (sotrovimab or nirmatrelvir/r or molnupiravir) between January 2022 and February 2024 (omicron phase). Demographic, clinical, and treatment-related data were analyzed to assess primary endpoints of 28-day mortality and hospitalization. Logistic regression models identified predictors of key outcomes. Results: A total of 668 high-risk patients treated with sotrovimab (n = 326) or oral antivirals (n = 342: 69 with molnupiravir and 273 with nirmatrelvir/ritonavir) were included. There was no significant difference in 28-day mortality between groups (0.8% sotrovimab vs. 1.8% oral antivirals; p = 0.679). However, patients treated with sotrovimab exhibited a longer median time to SARS-CoV-2 negativization (13 vs. 11 days; p = 0.008) and higher non–COVID-19-related hospitalizations (2.45% vs. 0%; p = 0.003). Multivariable analysis identified cardiovascular or cerebrovascular diseases as the sole significant predictor of prolonged viral positivity (OR 1.585, 95% CI 1.072–2.345; p = 0.021). Additionally, immunocompromised status (OR 16.929, 95% CI 1.835–156.170; p = 0.013) and chronic non-COVID-19 oxygen therapy (OR 10.714, 95% CI 1.623–70.725; p = 0.014) were strongly associated with mortality. Conclusions: Sotrovimab and oral antivirals demonstrated similar efficacy in preventing mortality and hospitalization among high-risk patients. Patient-specific factors, particularly cardiovascular comorbidities and immunosuppression, significantly influenced outcomes and should guide treatment choices.