Inactivation kinetics of endogenous lipoxygenase in crude silver carp (Hypophthalmichthys molitrix) extract was studied for thermal (50–80 °C, ambient pressure) and high hydrostatic pressure combined with heat treatment (300–700 MPa at 50–80 °C) process conditions. Lipoxygenase (LOX) inactivation followed first-order kinetics at all pressure–temperature combinations used. Moreover, LOX inactivation rates became less pressure dependent with increasing pressure at all temperatures studied and also showed less temperature dependence of the enzyme inactivation rate at various high pressure levels tested. It is evident that inactivation kinetics is complex affected by both pressure and temperature. Therefore, response surface methodology (RSM) was attempted to investigate combined temperature–pressure processing conditions on LOX inactivation kinetics in crude silver carp extract samples. In conclusion, the LOX inactivation rate constant was modelled as a function of both temperature and pressure conditions by a quadratic polynomial equation as follows: .