Identifying effective drugs for Coronavirus disease 2019 (COVID-19) is urgently needed. An efficient approach is to evaluate whether existing approved drugs have anti-SARS-CoV-2 effects. The antiviral properties of lithium salts have been studied for many years. Their anti-inflammatory and immune-potentiating effects result from the inhibition of glycogen synthase kinase-3. To obtain pre-clinical evidence on the safety and therapeutic effects of lithium salts in the treatment of COVID-19. Six different concentrations of lithium, ranging 2–12 mmol/L, were evaluated. Lithium inhibited the replication of SARS-CoV-2 virus in a dose-dependent manner with an IC50 value of 4 mmol/L. Lithium-treated wells showed a significantly higher percentage of monolayer conservation than viral control, particularly at concentrations higher than 6 mmol/L, verified through microscopic observation, the neutral red assay, and the determination of N protein in the supernatants of treated wells. Hamsters treated with lithium showed less intense disease with fewer signs. No lithium-related mortality or overt signs of toxicity were observed during the experiment. A trend of decreasing viral load in nasopharyngeal swabs and lungs was observed in treated hamsters compared to controls. These results provide pre-clinical evidence of the antiviral and immunotherapeutic effects of lithium against SARS-CoV-2, which supports an advance to clinical trials on COVID-19′s patients. Display omitted •Antiviral, anti-inflammatory and immune-potentiating effects of lithium salts have been described.•Lithium directly inhibits the replication of SARS-CoV-2 in Vero E6 cells in a concentration-dependent manner with an IC50 of 4 mmol/L.•Syrian hamsters treated with human therapeutic doses of lithium showed a less intense disease.