The benefits of remdesivir treatment, with or without co-administration of antibiotics such as azithromycin, are uncertain in COVID-19 pneumonia. The aim of this retrospective single-center study was to assess the effects of remdesivir, with or without azithromycin, on hospital mortality, intensive care unit (ICU) admission, and need of non-invasive ventilation. The clinical records of the COVID-19 patients hospitalized in an Italian ward in March 2021 were analyzed, and data on comorbidities and clinical, radiological, and laboratory presentation of the disease were collected. Among 394 participants (234 M), 173 received remdesivir (43.9%), including 81 with azithromycin (20.5%). Remdesivir recipients were younger, with less comorbidities, and had better PaO2/FiO2 and clinical outcomes, including reduced mortality, but the differences were not independent of covariates. Rates of ICU transferal were 17%, 9%, and 1% in the no remdesivir, remdesivir without azithromycin, and remdesivir/azithromycin groups, respectively. In a stepwise multivariate logistic regression model, remdesivir/azithromycin co-treatment was independently associated with reduced ICU admission (vs remdesivir alone, OR 0.081, 95% CI 0.008–0.789, p = 0.031; vs no remdesivir, OR 0.060, 95% CI 0.007–0.508, p = 0.010). These data suggest that the therapeutical effect of remdesivir in COVID-19 pneumonia may be potentiated by azithromycin. The association between the two drugs should be further investigated.