Background and objectives: Hyperthermia with dehydration alters several brain structure volumes, mainly by changing plasma osmolality, thus strongly affecting neural functions (cognitive and motor). Here, we aimed to examine whether the prevention of significant dehydration caused by passively induced whole-body hyperthermia attenuates peripheral and/or central fatigability during a sustained 2-min isometric maximal voluntary contraction (MVC). Materials and Methods: Ten healthy and physically active adult men (21 ± 1 years of age) performed an isometric MVC of the knee extensors for 2 min (2-min MVC) under control (CON) conditions, after passive lower-body heating that induced severe whole-body hyperthermia (HT, Tre > 39 °C) with dehydration (HT-D) and after HT with rehydration (HT-RH). Results: In the HT-D trial, the subjects lost 0.94 ± 0.15 kg (1.33% ± 0.13%) of their body weight; in the HT-RH trial, their body weight increased by 0.1 ± 0.42 kg (0.1% ± 0.58%). After lower-body heating, the HT-RH trial (vs. HT-D trial) was accompanied by a significantly lower physiological stress index (6.77 ± 0.98 vs. 7.40 ± 1.46, respectively), heart rate (47.8 ± 9.8 vs. 60.8 ± 13.2 b min−1, respectively), and systolic blood pressure (−12.52 ± 5.1 vs. +2.3 ± 6.4, respectively). During 2-min MVC, hyperthermia (HT-D; HT-RH) resulted in greater central fatigability compared with the CON trial. The voluntary activation of exercising muscles was less depressed in the HT-RH trial compared with the HT-D trial. Over the exercise period, electrically (involuntary) induced torque decreased less in the HT-D trial than in the CON and HT-RH trials. Conclusions: Our results suggest that pre-exercise rehydration might have the immediate positive effect of reducing physiological thermal strain, thus attenuating central fatigability even when exercise is performed during severe (Tre > 39 °C) HT, induced by passive warming of the lower body.