Background: Physical fatigue and cognitive performance have been suggested as risk factors for an anterior cruciate ligament (ACL) injury, and fatigue has also been demonstrated to reduce cognitive processing. The combined effects of fatigue and lower cognitive function during cognitive-challenging movements may increase knee mechanics associated with the ACL injury risk. Hypotheses: We hypothesized that (1) knee mechanics would be detrimentally affected by fatigue and associated with baseline cognitive function and (2) fatigue-induced deleterious changes in cognitive performance and knee mechanics would be correlated. Study Design: Descriptive laboratory study. Methods: A total of 22 athletes completed baseline cognitive testing. After performing maximal vertical jumps, they performed a jump-land-jump task based on unanticipated visual cues. Then, they completed a fatigue protocol including countermovement jumps, among other tasks, until the jump height decreased below 90% of their assessed maximum. Immediately after reaching the first fatigue point, they performed another set of jump-landing tasks, followed by repeating the fatigue protocol until the jump height decreased below 85% of their assessed maximum. After reaching the second fatigue point, they performed a final set of jump-landing tasks and repeated the initial cognitive assessment battery. Results: Mixed-effects models revealed that knee flexion decreased through the fatigue protocol (baseline: 61.8°; midpoint: 61.1°; final: 60.1°; P = .003). Stepwise regression showed that fatigue-worsened attentional control corresponded to smaller knee abduction angles ( R²_adjusted = 51.68%; β_standardized = 1.16; P = .001), and worse reaction time after fatigue correlated with increased knee abduction angles (β_standardized = 0.85; P = .006) after accounting for the role of attentional control. Conclusion: Fatigue induced incremental modifications in sagittal-plane knee mechanics during an unanticipated sports movement. In addition, fatigue induced changes in cognitive function related to ACL injury–relevant knee mechanics. Clinical Relevance: The novel findings regarding fatigue-dependent changes in injury-relevant biomechanics during cognitively challenging movements represent an extension of recent developments in understanding the role of cognition in the ACL injury risk.