Background: Currently, cold atmospheric plasma (CAP) technology has been developing and its medical applications such as skin decontamination, tooth bleaching, wound healing, and cancer therapy have been vigorously studying. Objectives: With very limited number of the experiments were performed in vivo, the purpose of this study was to verify and demonstrate CAP’s anti-cancer effect in syngeneic mouse model. Methods: The effect of CAP treatment on viability of HaCat cells, B16F10 melanoma, and MC38 colon cancer cells was determined in vitro. Syngeneic mouse tumor model was made by injecting 5x105 of B16F10 or MC 38 cells into each mouse (n = 20 for B16F10 melanoma model and n = 21 for MC38 colon cancer model). After the growth of tumors, experimental groups were treated with CAP every other day for 5 times. Tumor volume and weight were measured at each time point, and tumor growth inhibition (TGI) was calculated at day 10. On day 10, all tumors were excised to evaluate histologically Results: CAP treatment significantly decreased cell viability of both B16F10 and MC38 cell lines, while CAP treatment showed negligible effect on cell viability of HaCat cells. In vivo experiments, tumor volume and weight were decreased significantly more in CAP treated groups compared to the control groups regardless of tumor cell types. Conclusion: This preliminary study reveals the effect of CAP on inhibiting tumor growth in mouse melanoma and colon cancer cell lines both in vitro and in vivo.