Procambarus clarkii (red swamp crayfish) exhibits physiological plasticity that enables adaptation to variable freshwater conditions, such as those in Lake Trasimeno. This study examined whether fluctuations in hydrometric level and associated physicochemical parameters affect oxidative stress responses in the hepatopancreas and abdominal muscle of male and female individuals. Superoxide dismutase, catalase, glutathione peroxidase, and metallothionein reveal tissue, sex, and season-specific differences that indicate adaptive physiological adjustments. Temporal trends were evaluated, and multivariate analyses summarised environmental and metal gradients. Generalised Additive Models (GAMs) were used to explore relationships between oxidative responses and these gradients, with sex as a categorical factor. Associations were identified with hydrometric level, temperature, conductivity, transparency, pH, dissolved oxygen, and metals of biological relevance. These results highlight the remarkable physiological plasticity of P. clarkii, which underpins its success as an invasive species in fluctuating freshwater ecosystems.