KAATSU training at greatly reduced intensities has been proven to result in substantial increases in both muscle hypertrophy and strength. Nevertheless, this revolutionary training method (combined with the restriction of venous blood flow from the working muscle) may cause underlying hypoxia and neurotransmitter dysfunction, which are linked to neuromuscular fatigue. Hence, an exploration of KAATSU training-induced hypoxic and neurodegenerative events is of utmost importance before promoting this training mode, although KAATSU has been shown to result in numerous positive training adaptations. Furthermore, based on substantial evidence, L-carnitine supplementation exerts neuroprotective effects by attenuating hypoxic stress and neurotransmitter dysfunction. However, studies directly examining the effects of KAATSU exercise on both hypoxia and neurotransmitter dysfunction, which would aggravate the detrimental effects of neuromuscular fatigue, are lacking. In addition, an expansion of the applications of L-carnitine to a smaller-molecule field for treating KAATSU training-evoked neuromuscular fatigue requires further clarification. Therefore, this review aims to present the current evidence for the effectiveness of exogenous L-carnitine at reducing the amount of hypoxic damage and its neuroprotective effects mediated by increasing cerebral acetylcholine levels. Simply, L-carnitine administration may be an important contributor to the mechanisms curtailing KAATSU training-induced neuromuscular fatigue.