Muscle fatigue is associated with reduced power output and work capacity of the skeletal muscle. Fatigue-induced impairments in muscle function are believed to be a potential cause of increased injury rates during the latter stages of athletic competition and often occur during unexpected perturbations. However the effect of fatigue on functionally relevant, full body destabilizing perturbations has not been investigated. This study examines the effect of muscle fatigue on the activation of the quadriceps and hamstrings to fast, full body perturbations evoked by a moveable platform. Surface electromyographic (EMG) signals were recorded from the knee extensor (vastus medialis, rectus femoris, and vastus lateralis) and flexor muscles (biceps femoris and semitendinosus) of the right leg in nine healthy men during full body perturbations performed at baseline and immediately following high intensity exercise performed on a bicycle ergometer. In each condition, participants stood on a moveable platform during which 16 randomized postural perturbations (eight repetitions of two perturbation types: 8 cm forward slides, 8 cm backward slides) with varying inter-perturbation time intervals were performed over a period of 2-3 min. Maximal voluntary knee extension force was measured before and after the high intensity exercise protocol to confirm the presence of fatigue. Immediately after exercise, the maximal force decreased by 63% and 66% for knee extensors and flexors, respectively (P<0.0001). During the post-exercise postural perturbations, the EMG average rectified value (ARV) was significantly lower than the baseline condition for both the knee extensors (average across all muscles; baseline: 19.7±25.4μV, post exercise: 16.2±19.4 μV) and flexors (baseline: 24.3±20.9 μV, post exercise: 13.8±11.0 μV) (both P<0.05). Moreover the EMG onset was significantly delayed for both the knee extensors (baseline: 132.7±32.9 ms, post exercise: 170.8±22.9 ms) and flexors (baseline: 139.1±38.8 ms, post exercise: 179.3±50.9 ms) (both P<0.05). A significant correlation (R(2)=0.53; P<0.05) was identified between the percent reduction of knee extension MVC and the percent change in onset time of the knee extensors post exercise. This study shows that muscle fatigue induces a reduction and delay in the activation of both the quadriceps and hamstring muscles in response to rapid destabilizing perturbations potentially reducing the stability around the knee.