Gastric cancer is a malignancy with high incidence and the second leading cause of cancer death worldwide. Development of efficient therapies against gastric cancer is urgent. Until now, the mechanisms of gastric cancer genesis remain elusive. The KDM5C is a histone demethylase that promotes cancer cell growth and is enriched in drug-resistant cancer cells. But the pathogenic breadth and mechanistic aspects of this effect relative to gastric cancer have not been defined. In present study, we found that KDM5C was overexpressed in gastric cancer cell lines and gastric cancer tissues but not in normal gastric tissues. The proliferation and invasive potential of gastric cancer cells was significantly increased by ectopic expression of KDM5C. Contrarily, RNA interference targeting KDM5C in gastric cancer cells significantly decreased the proliferation and invasive potential of cells. Moreover, we also found that the expression of p53 was modulated by KDM5C. Cells with overexpression of KDM5C exhibited greatly decreased p53 expression, whereas silencing of KDM5C expression dramatically increased p53 expression at both the messenger RNA and protein levels. Inhibition of p53 by small-interfering RNA reversed the shKDM5C-induced proliferation and invasion. Our results collectively suggested that KDM5C played a role in gastric cancer cells proliferation and invasion, which may be partly associated with the p53 expression.