White et al. identified the limitations of the current care standards for COVID-19 (remdesivir and dexamethasone). Alternatively, they suggest plitidepsin as a potential treatment for SARS-CoV-2 exhibiting antiviral activity. Plitidepsin targets the host protein eEF1A, known to interact with the proteins of SARS-CoV-2, proven by a previous experiment with a drug-resistant mutant (A399V) of eEF1A verifying that the antiviral activity is due to the eEF1A inhibition pathway. The antiviral efficacy of plitidepsin inhibiting the SARS-CoV-2 replication in a human cell line (hACE2-293T) was represented by the 90% inhibitory concentration (IC90) of 0.88nM, having 27.5-fold more than remdesivir, which is currently used for antiviral treatment during COVID-19 emergency. Phase I/II clinical studies of plitidepsin used to treat various myeloma confirmed the safety profile of plitidepsin, not having a significant adverse effect. The current study includes tests of two different established animal models for in vivo efficacy. For both models, BALB/c mice expressing human ACE2 and K18-hACE2, results showed the reduction of SARS-CoV-2 from the lung viral titer by two orders of magnitude and reduced lung inflammation (histopathology score of 1/16). The findings of this study establish plitidepsin as a host-targeted anti-SARS-CoV-2 agent with in vivo efficacy. Strong consideration is suggested for expanded clinical trials of COVID-19 treatment with plitidepsin.