Total phenolic contents of different fractions of the Psidium cattleianum leaf extract and their antioxidant capacity against several free radicals were examined. Protective effect of the ethyl acetate fraction (EAF) on $H_2O_2$-induced DNA damage in HepG2 cells were also evaluated, and the phytochemical profile of EAF was analyzed using tandem mass spectrometry. EAF derived from the 80% methanol extract of the leaf contained a remarkable amount of polyphenol and showed high levels of DPPH and alkyl radical scavenging activity, promoted cell viability, and protected against $H_2O_2$-induced DNA damage in HepG2 cells. Phytochemical analysis revealed that the major components in the EAF included quercetin monoglycoside, phloridizin, quercetin 3-diglycoside, quercetin-3-glucuronide, 2,6-dihydroxy-3,5-dimethyl-4-glucopyranosyl-benzophenone, phenolic acid, guaijaverin, and naringin. The present study suggests possible synergistic or competitive antioxidant action of the major compounds of cattley guava leaf on $H_2O_2$-induced DNA damage in HepG2 cells. These results indicate that the ethyl acetate fraction of the guava leaf could be used as a potential source of natural antioxidants, and these findings will facilitate the utilization of guava leaf as a source of functional food.