Background and Objectives: Considering the significant number of patients worldwide that received empirical antibiotic therapy for COVID-19 infection due to their critical condition and the lack of therapeutical guidelines, we wanted to find out the consequences of antibiotic use in our study population. Materials and Methods: We conducted a retrospective cohort study including symptomatic patients older than 18 years, hospitalized for SARS-CoV-2 between March and December 2020 in the Internal Medicine and Pneumology Departments of Colentina Clinical Hospital. The elected outcome was death, while independent variables were antibiotic therapy and literature-cited parameters associated with mortality in this disease. Results: Out of 198 included patients, 96 (48.48%) patients received antibiotic therapy during hospitalization. Female gender (OR = 2.61, p = 0.04), history of neoplasm (OR = 7.147, p = 0.01), heart failure (OR = 8.62, p = 0.002), and diabetes mellitus (OR = 3.05, p = 0.02) were significantly associated with death in multivariate analysis. Antibiotic treatment showed a higher probability of death both in bivariate (OR = 5.333, p < 0.001) and multivariate analysis adjusted for the aforementioned prognostic factors (OR = 3.55, p = 0.01). Conclusions: After adjusting for confounders, in-hospital antibiotic administration did not improve survival in COVID-19 patients.