Recently, CeNPs have emerged as an effective therapeutic agent due to their redox-active nature encompassing the ability to switch between +4 or +3 oxidation states of surface "Ce" atoms. CeNPs with predominantly high Ce +4 oxidation state have been shown to exhibit biological catalase enzyme-like activity. Catalase enzyme is naturally present in mammalian cells and facilitates the protection from reactive oxygen species (ROS), generated due to decomposition of hydrogen peroxide (H2O2). Inactivation of cellular catalase enzyme is known to cause several diseases such as acatalasemia, type 2 diabetes mellitus, and vitiligo. In this study, we have artificially inhibited the activity of cellular catalase enzyme from human liver cells (WRL-68) using 3-Amino-1,2,4-Triazole (3-AT). Further, CeNPs was used for imparting protective effect against the deleterious effects of elevated cellular H2O2 concentration. Our results suggest that CeNPs (+4) can protect hepatic cells from cytotoxicity and genetic damage from the high concentrations of H2O2 in the absence of functional catalase enzyme. CeNPs were efficiently internalized in WRL-68 cells and effectively scavenge the free radicals generated due to elevated H2O2 inside the cells. Additionally, CeNPs were also shown to protect cells from undergoing early apoptosis and DNA damage induced due to the 3-AT exposure. Moreover, CeNPs did not elicit the natural antioxidant defense system of the cells even in the absence of functional catalase enzyme, suggesting that the observed protection was due to the H2O2 degradation activity of CeNPs (+4). Our finding substantiates the reinforcement of CeNPs as pharmacological agents for the treatment of diseases related to nonfunctional biological catalase enzyme in the mammalian cells.