Abstract Global climate change represents a critical threat to the environment since it influences organismic interactions, such as the host-parasite systems, mainly in ectotherms including fishes. Rising temperature and CO2 are predicted to affect this interaction other and critical physiological processes in fish. Herein, we investigated the effects of different periods of exposure to climate change scenarios and to two degrees of parasitism by monogeneans in the host-parasite interaction, as well as the antioxidant and ionoregulatory responses of tambaqui (Colossoma macropomum), an important species in South American fishing and aquaculture. We hypothesized that temperature and CO2 changes in combination with parasite infection would interfere with the host’s physiological processes that are related to oxidative stress and ionoregulation. We experimentally exposed C. macropomum to low and high levels of parasitism in the current and extreme climate scenarios (4.5 °C and 900 ppm CO2 above current levels) for periods of seven and thirty days and we use as analyzed factors; the exposure time, the climate scenario and parasitism level in a 2 × 2 × 2 factorial through a three-way ANOVA as being fish the experimental unit (n = 8). An analysis of gill enzymatic and gene expression profile was performed to assess physiological (SOD, GPx and Na+/K+-ATPase enzymes) and molecular (Nrf2, SOD1, HIF-1α and NKA α1a genes) responses. A clear difference in the parasitism levels of individuals exposed to the extreme climate scenario was observed with a rapid and aggressive increase that was higher after 7 days of exposure though showed a decrease after 30 days. The combination of exposure to the extreme climate change scenario and parasitism caused oxidative stress and osmoregulatory disturbance, which was observed through the analysis of gene expression (Nrf2, SOD1, HIF-1α and NKA α1a) and antioxidant and ionoregulatory enzymes (SOD, GPx and Na+/K+-ATPase) on the host, possibly linked to inflammatory processes caused by the high degree of parasitism. In the coming years, these conditions may result in losses of performance for this species, and as such will represent ecological damage and economical losses, and result in a possible vulnerability in relation to food security.