A huge challenge after the emergence of COVID-19 has been the discovery of effective antiviral drugs. Although remdesivir (RDV) emerged as one of the most promising drugs, its pharmaceutical formulation Veklury® is limited by moderate efficacy, high toxicity and need for parenteral administration. The aim of the present work was to develop a liposomal formulation of RDV for pulmonary administration and evaluate its efficacy in models of COVID-19. Liposomal RDV nanoformulation (LRDV) was selected based on high drug encapsulation efficiency, sustained drug release property and high in vitro selectivity index. A pharmacokinetic study of intranasal LRDV in mice demonstrated effective delivery of the drug to the lungs. LRDV was then evaluated for its efficacy in SARS-CoV-2-infected K18-hACE2 mice after repeated intranasal administration at 10 mg/kg/bid for 5 days. Veklury® given intraperitoneally at 20 mg/kg/bid was used for comparison. Mice receiving LRDV remained alive up to 15 days post-infection (dpi). On the other hand, the control groups receiving PBS and empty liposomes showed 100 % death at 6 dpi and the Veklury® group had 62.5 % death at 8 dpi. Intranasal LRDV also promoted a strong reduction in viral loads in the brain and lungs of mice and prevented the inflammatory response induced by SARS-CoV-2 in the lungs. This is in contrast with Veklury®, which did not significantly reduce the viral titer in the brain and was poorly effective in preventing the inflammatory response in the lungs. Intranasal LRDV emerges as a promising therapeutic strategy for COVID-19, including "Long COVID".