The antiviral activity and protective mechanism of Korean red ginseng (KRG) is not well understood. The aim of this study was to investigate the protective mechanism of KRG extract and ginsenosides against feline calicivirus (FCV), a human norovirus surrogate. CRFK cells that were pretreated for 48h with 10μg/mL of KRG extract or purified ginsenoside Rb1 or Rg1, were inoculated with FCV. RNA extracted from each treated group was examined for the expression of antiviral cytokines, including interferon-α (IFN-α), interferon-β (IFN-β), interferon-ω (IFN-ω), Mx, and zinc finger antiviral protein shorter isoform (ZAPS), by relative real-time reverse transcription-polymerase chain reaction. mRNA expression of IFN-α, IFN-β, IFN-ω, Mx, and ZAPS was significantly induced in the FCV-challenged group pretreated with the KRG extract or ginsenosides, and it was higher than the group treated with FCV alone. Mx protein expression was confirmed by western blotting of CRFK cells pretreated with the ginsenoside Rb1 or with Rg1. Induction of antiviral cytokines contributes to the reduction of the viral titer in CRFK cells pretreated with the KRG extract and purified ginsenosides. In future studies, the antiviral protective mechanism of KRG should be demonstrated using other viruses such as human norovirus.