The critical role of ecological preferences and opportunity in determining contaminant uptake and adaptive responses of sexes in the wild is still poorly understood. This ecological relationship was investigated by measuring metal bioaccumulation and antioxidant activity in male and female blue crab populations from open water habitat and the littoral/inter‐tidal zone of the Lagos Lagoon. A total of 741 samples of blue crab (littoral zone: 263 females, 137 males; open water zone, 230 females, 111 males) was collected monthly over 24 months (January 2010–January 2012) from each site and the measurements of morphometric features (wet weight, carapace length, carapace width) were recorded; condition index, metal (redox active: Cu, Zn, redox inactive: Pb, Cd) concentration in tissues (gills, hepatopancreas, gonads and muscle) and antioxidant activity (superoxide dismutase, reduced glutathione, glutathione peroxidase, catalase and malondialdehyde) were measured for each sex. Monthly sediment samples for both habitats were also analysed for metals using standard methods. Female crabs were significantly larger (p < .05) with a better condition index than the male crabs across sites and seasons, while higher oxidative damage was recorded in male crabs in the littoral zone compared to the open water zone. The results show that there was a negative association between antioxidant activity and lipid peroxidation; a negative relationship between concentrations of redox‐inactive metals (Pb and Cd) and antioxidant activity in male crab tissues; and a positive relationship between uptake of a redox‐active metal (Cu) and antioxidant activity in female crab tissues. Although these trends suggest sex‐specific toxicity, they also associate redox‐inactive metals with the downregulation of antioxidant activity and oxidative stress. Furthermore, the higher condition index of females corroborates the possibility of sex‐specific toxicity, while the larger‐sized females compared to males suggests size‐sexual dimorphism in the blue crab populations. The site‐specific oxidative damage between sexes may be attributed to the different complexity of both habitats, which affords different ecological opportunities for the sexes.