Since there is no vaccine or regulatory approved therapy available for treatment of SARS-CoV-2 infection, the medical need to prevent the transition of a mild into the severe COVID-19 stage of infection is of outmost importance. Among several drug candidates, Chloroquine (CQN) and Hydroxy-Chloroquine (H-CQN) have been tested most intensively. However, the therapeutic effect of H-CQN and CQN has been discussed controversially in the light of severe side effects. Originally, H-CQN descended from the natural substance Quinine, a medicinal product used since the Middle Ages and is now regulatory approved for various indications. We hypothesized that Quinine also exerts anti-SARS-CoV-2 activity. First, virus production in Vero B4 cells was analyzed by Western blot, showing that Quinine exerts antiviral activity against SARS-CoV-2 that at 10 µM was even stronger than that of H-CQN or CQN. Second, fluorescence end-point and time lapse analysis of SARS-CoV-2-mNeonGreen-infected Caco-2 cells could confirm a similar antiviral effect of Quinine in a human-derived cell line. Thereby, our in vitro studies revealed, that the antiviral effect appears to be specific, since in Vero cells Quinine impacted cell viability at approximately 50-fold higher concentration, while the therapeutic window of H-CQN and CQN was approximately 10-fold lower. In Caco-2 cells no toxic effect was observed while complete block of infection occurred between 50 and 100 µM at high MOIs. In conclusion, our data indicate that Quinine would have the potential of a well tolerable and widely used treatment option for SARS-CoV-2 infections, with a predictable and significantly better toxicological profile when compared to H-CQN or CQN.