Background Whole-Body Cryotherapy (WBC) - a repetitive, short-term exposure to extremely low temperatures – may become an effective early intervention for mild cognitive impairment (MCI). It is a heterogeneous group of symptoms associated with cognitive dysfunction which is estimated to transform into dementia in 50% cases. Study design The prospective randomised double-blind sham-controlled study aimed to determine the efficacy of WBC on cognitive functioning and biological mechanisms. The study was registered with Australian New Zealand Clinical Trials Registry (ACTRN12619001627145). Methods Participants with MCI (n = 62; (2026) were randomly allocated to cryogenic temperatures (−110 °C till −160 °C) (EG, n = 33) or placebo-controlled group (CG, n = 29). Cognitive functions were measured at baseline (T1), after the 10th WBC session (T2) and after 2 week-break (T3) with DemTect, SLUMS and Test Your Memory (TYM). Secondary outcome measures included quality of life (WHOQoL–BREF), self-reported well-being (VAS) and depressive symptoms (GDS). Whole blood samples (10 ml) were collected at T1 and T2 to evaluate levels of cytokines, neurotrophins, NO and biochemical parameters CRP total cholesterol, prolactin). Results There were significant differences between groups measured at T2 in immediate recall (DemTect) and in orientation (TYM) in favour of WBC group. Improvement in mood was detected in self-reported depressive symptoms level (WHOQoL-26; T2 p = 0.04; VAS mood T2 p = 0.02; T3 p = 0.07). The significant reduction of BDNF level was observed (p < 0.05). Conclusions WBC may increase the performance of cognitive functions. It seems promising to combine WBC with existing behavioural and cognitive trainings in the future studies investigating early interventions methods in MCI.