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The unprecedented coronavirus disease pandemic of 2019 (COVID-19) caused by the second severe acute respiratory syndrome virus (SARS-CoV-2) poses a serious threat to public health worldwide. There is an urgent need to develop effective therapies against SARS-CoV-2. We evaluated the antiviral activity of the original remdesivirus nucleotide analog, GS441524, which targets the enzyme RNA-dependent RNA polymerase, and the protease inhibitor GC376, which targets the protease SARS-CoV 2 in infected mice. Our results showed that GS441524 effectively blocked SARS-CoV-2 proliferation (multiplication) in the upper and lower airways with combined intranasal (in) and intramuscular (im) therapy. The efficacy of the high dose of GC376 (im or in and im) was weaker than GS441524. However, it is noteworthy that the combined administration of GS441524 together with GC376 at low doses could effectively protect mice from SARS-CoV-2 infection during in or in and their treatment. We further found that the pharmacokinetic properties of GS441524 were superior to GC376, and the combined application of GC376 and GS441524 had a synergistic effect. Our findings will be used to further evaluate the combined application of GC376 and GS441524 in future clinical trials.