<p>The hypoxic zone in the northern Gulf of Mexico varies spatially (area, location) and temporally (onset, duration) on multiple scales. Exposure to hypoxic dissolved oxygen (DO) concentrations (< 2 mg L<sup>−1</sup>) is often lethal and exposure to 2 to 4 mg L<sup>−1</sup> often causes the sublethal effects of decreased growth and fecundity on individuals of many fish species. We simulated the movement of individual fish within a high-resolution 3-D coupled hydrodynamic-water quality model (FVCOM-WASP) configured for the northern Gulf of Mexico to examine how spatial variability in DO concentrations would affect fish exposure to hypoxic and sublethal DO concentrations. Eight static snapshots (spatial maps) of DO were selected from a 10 day FVCOM-WASP simulation that showed a range of spatial variation (degree of clumpiness) in sublethal DO area from moderate total sublethal area (4 maps) to high total sublethal area (4 maps). An additional case of allowing DO to vary in time (dynamic DO) was also included. All simulations were for 10 days and were performed for 2-D (bottom layer only) and 3-D (allows for vertical movement of fish) sets of maps. Fish movement was simulated every 15 minutes using one of three algorithms designed for avoiding low DO exposure and a default algorithm not dependent on DO conditions. Fish were assumed to have either good or poor avoidance competencies. Cumulative exposure of individuals to hypoxia was higher under the high sublethal area snapshots compared to the moderate sublethal area snapshots. The effects of different degrees of spatial variability on hypoxia exposure were small. Despite the differences in exposure to hypoxia with good versus poor competency, both resulted in relatively high exposures to sublethal DO concentrations. Spatial variability in DO had opposite effects on sublethal exposure between moderate and high sublethal area maps: the percentage of fish exposed to 2–3 mg L<sup>−1</sup> decreased with increasing variability for high sublethal area but increased for moderate sublethal area. There was a substantial inter-individual variability in exposure to hypoxic and sublethal DO that, when combined with spatial variability in DO, can result in underestimation of sublethal effects (e.g., growth) when exposure of individuals is averaged by spatial cells. By following hundreds of thousands of individuals over multiple generations within 3-D hydrodynamic-water quality models, we aim to predict fish population-level responses to hypoxia under management actions designed to reduce nutrient inputs.</p>