(1) Background: Large cohort studies of patients with COVID-19 treated with remdesivir have reported improved clinical outcomes, but data on older patients are scarce. Objective: This work aims to assess the potential benefit of remdesivir in unvaccinated very old patients hospitalized with COVID-19; (2) Methods: This is a retrospective analysis of patients ≥ 80 years hospitalized in Spain between 15 July and 31 December 2020 (SEMI-COVID-19 Registry). Differences in 30-day all-cause mortality were adjusted using a multivariable regression analysis. (3) Results: Of the 4331 patients admitted, 1312 (30.3%) were ≥80 years. Very old patients treated with remdesivir (n: 140, 10.7%) had a lower mortality rate than those not treated with remdesivir (OR (95% CI): 0.45 (0.29–0.69)). After multivariable adjustment by age, sex, and variables associated with lower mortality (place of COVID-19 acquisition; degree of dependence; comorbidities; dementia; duration of symptoms; admission qSOFA; chest X-ray; D-dimer; and treatment with corticosteroids, tocilizumab, beta-lactams, macrolides, and high-flow nasal canula oxygen), the use of remdesivir remained associated with a lower 30-day all-cause mortality rate (adjusted OR (95% CI): 0.40 (0.22–0.61) (p < 0.001)). (4) Conclusions: Remdesivir may reduce mortality in very old patients hospitalized with COVID-19.