Purpose: We aimed to investigate respiratory rate variability (RRV) and tidal volume (Vt) variability during exposure to normobaric hypoxia (i.e., reduction in the fraction of inspired oxygen - FiO2), and the association of the changes in RRV and Vt variability with the changes in pulse oxygen saturation (SpO2). Methods: Thirty healthy human participants (15 females) were exposed to: (1) 15-min normoxia, (2) 10-min hypoxia simulating 2200 m, (3) 10-min hypoxia simulating 4000 m, (4) 10-min hypoxia simulating 5000 m, (5) 15-min recovery in normoxia. Linear regression modelling was applied with SpO2 (dependent variable) and the changes in RRV and Vt variability (independent variables), controlling for FiO2, age, sex, changes in heart rate (HR), changes in HR variability (HRV), and changes in minute ventilation (VE). Results: When modelling breathing parameter variability as root-mean-square standard deviation (RMSSD), a significant independent association of the changes in RRV with the changes in SpO2 was found (B = -4.3e-04, 95% CI = -8.3e-04/-2.1e-05, p = 0.04). The changes in Vt variability showed no significant association with the changes in SpO2 (B = -1.6, 95% CI = -5.5/2.4, p = 0.42). When modelling parameters variability as SD, a significant independent association of the changes in RRV with the changes in SpO2 was found (B = -8.2e-04, 95% CI = -1.5e-03/-9.4e-05, p = 0.03). The changes in Vt variability showed no significant association with the changes in SpO2 (B=1.4, 95% CI = -5.8/8.6, p = 0.69). Conclusion: Higher RRV is independently associated with lower SpO2 during acute hypoxic exposure, while Vt variability parameters are not. Therefore, RRV may be a potentially interesting parameter to characterize individual responses to acute hypoxia.