Purpose The aim of the present investigation was to determine whether a one-hour floatation-REST session could augment recovery from high-intensity resistance exercise (6 x10 back squats, 2 minutes rest) known to induce significant metabolic, adrenergic, and mechanical stress. Methods Eleven healthy resistance-trained males (age: 22.5 ± 2.3 years; height: 176.4 ± 6.0 cm; weight: 85.7 ± 6.2 kg, back squat 1RM: 153.1 ± 20.1 kg; strength to weight ratio: 1.8 ± 0.2) completed the within-subjects, cross-over controlled study design. Participants completed two exercise testing blocks separated by a two-week washout. In one block, the high-intensity resistance exercise protocol was followed by a one-hour floatation-REST session, while recovery in the alternate block consisted of a passive sensory-stimulating control. Markers of metabolic stress, neuroendocrine signaling, structural damage, inflammation, and perceptions of soreness, mood state and fatigue were assessed over a 48-hour recovery window. Results Floatation-REST significantly attenuated muscle soreness across recovery (p = 0.035) with greatest treatment difference immediately following the intervention (p = 0.002, ES = 1.3). Significant differences in norepinephrine (p = 0.028, ES = 0.81) and testosterone (p = 0.028, ES = 0.81) immediately following treatment revealed modification of neuroendocrine signaling pathways which were accompanied by greater improvements in mood disturbance (p = 0.029, ES = 0.81) and fatigue (p = 0.001, ES = 1.04). Conclusions As no adverse effects and significant and meaningful benefits were observed, floatation-REST may prove a valuable intervention for managing soreness and enhancing performance readiness following exercise.