Heterogeneous Fenton reactions have been proven to be an effective and promising selective cancer cell treatment method. The key working mechanism for this method to achieve the critical therapeutic selectivity however remains unclear. In this study, we proposed and demonstrated for the first time the critical role played by catalase in realizing the therapeutic selectivity for the heterogeneous Fenton reaction-driven cancer cell treatment. The heterogeneous Fenton reaction, with the lattice ferric ions of the solid catalyst capable of converting HO to highly reactive hydroxyl radicals, can effectively eradicate cancer cells. In this study, SnFeO nanocrystals, a recently discovered outstanding heterogeneous Fenton catalyst, were applied for selective killing of lung cancer cells. The SnFeO nanocrystals, internalized into the cancer cells, can effectively convert endogenous HO into highly reactive hydroxyl radicals to invoke an intensive cytotoxic effect on the cancer cells. On the other hand, catalase, present at a significantly higher concentration in normal cells than in cancer cells, remarkably can impede the apoptotic cell death induced by the internalized SnFeO nanocrystals. According to the results obtained from the in vitro cytotoxicity study, the relevant oxidative attacks were effectively suppressed by the presence of normal physiological levels of catalase. The SnFeO nanocrystals were thus proved to effect apoptotic cancer cell death through the heterogeneous Fenton reaction and were benign to cells possessing normal physiological levels of catalase. The catalase modulation of the involved heterogeneous Fenton reaction plays the key role in achieving selective cancer cell eradication for the heterogeneous Fenton reaction-driven cancer cell treatment.