Pressurized hot water extracts obtained at different temperatures possess different compositions and antioxidant activities and, consequently, different bioactivities. We characterized two pressurized hot water extracts from grape pomace obtained at 100 °C (GPE100) and 200 °C (GPE200) in terms of antioxidant activity and composition, as well as protective effect on cell growth and mitochondrial membrane potential (Δψm) in a HL-60 cell culture under oxidative conditions. GPE100 extracts were richer in polyphenols and poorer in Maillard reaction products (MRPs) than were GPE200 extracts. Moreover, hydroxymethylfurfural was detected only in GPE200. Both extracts exhibited similar protective effects on cell growth (comparable to the effect of trolox). In addition, GPE100 strongly decreased the Δψmloss, reaching values even lower than those of the control culture. This protective effect may be related to its high polyphenols content. At the highest concentration assessed, both extracts showed strong cytotoxicity, especially GPE200. This cytotoxicity could be related to their MRPs content.