Purpose: The purpose of this study was to examine the composite, intra-individual, and inter-individual patterns of responses for deoxygenated hemoglobin and myoglobin (deoxy[heme]), oxygenated hemoglobin and myoglobin (oxy[heme]), total hemoglobin and myoglobin (total[heme]), and tissue saturation index (StO2%) during fatiguing, maximal, isokinetic, unilateral, and bilateral leg extensions. Methods: Nine men (Mean ± SD; age = 21.9 ± 2.4 years; height = 181.8 ± 11.9 cm; body mass = 85.8 ± 6.2 kg) performed 50 unilateral and bilateral maximal, concentric, isokinetic leg extensions at 180° s−1 on two separate visits. The muscle oxygenation parameters assessed with near-infrared spectroscopy from the dominant leg and isokinetic torque were averaged for 2 consecutive repetitions at 5 repetition intervals. Separate 2 (Condition [Unilateral and Bilateral]) × 10 (Repetition [5–50]) repeated measures ANOVAs were performed to examine mean differences for normalized isokinetic torque and each muscle oxygenation parameter. Intra- and inter-individual differences were examined with polynomial regression analyses. Results: For normalized isokinetic torque, the unilateral condition (56.3 ± 10.5%) exhibited greater performance fatigability than the bilateral condition (45.0 ± 18.7%). Collapsed across Condition, deoxy[heme] exhibited an increase (p < 0.001), while StO2% exhibited a decrease (p < 0.001). The bilateral condition exhibited a more sustained decline in oxy[heme] than the unilateral condition (p = 0.005). Deoxy[heme], oxy[heme], and total[heme] exhibited substantial intra- and inter-individual differences for the fatigue-induced patterns of response. Conclusion: The present findings indicated that the greater performance fatigability for unilateral versus bilateral fatiguing, maximal, isokinetic leg extensions was not attributable to differences in muscle oxygenation. Future studies of muscle oxygenation should report individual and composite fatigue-induced patterns of responses due to the substantial intra- and inter-individual variabilities.