Female-biased mortality has been repeatedly reported in Pacific salmon during their upriver migration in both field studies and laboratory-holding experiments, especially in the presence of multiple environmental stressors, including thermal stress. Here we used coho salmon (Oncorhynchus kisutch) to test whether females exposed to elevated water temperatures (18°C) i) suppress circulating sex hormones (testosterone, 11-ketotestosterone, and estradiol), owing to elevated cortisol levels, ii) have higher activities of enzymes supporting anaerobic metabolism (e.g., lactate dehydrogenase), iii) lower activities of enzymes driving oxidative metabolism (e.g., citrate synthase; CS), in skeletal and cardiac muscle, and iv) have more oxidative stress damage and reduced capacity for antioxidant defense (lower catalase activity; CAT). We found no evidence that a higher susceptibility to oxidative stress contributes to female-biased mortality at warm temperatures. We did, however, find that females had significantly lower cardiac LDH and that 18°C significantly reduced plasma levels of testosterone and estradiol, especially in females. We also found that relative gonad size was significantly lower in the 18°C treatment regardless of sex, whereas relative liver size was significantly lower in females held at 18°C. Further, relative spleen size was significantly elevated in the 18°C treatments across both sexes, with larger warm-induced increases in females. Our results suggest that males may better tolerate bouts of cardiac hypoxia at high temperature, and that thermal stress may also disrupt testosterone- and estradiol-mediated protein catabolism, and the immune response (larger spleens) in migratory female salmon.