The assessment of cerebral autoregulation (CA) relies mostly on methods that modulate arterial blood pressure (ABP). Despite advances, the gold standard of assessment remains elusive and clinical practicality is limited. We investigate a novel approach of assessing CA, consisting of the intermittent application of thigh cuffs using square wave sequences. Our aim was to increase ABP variability whilst minimizing volunteer discomfort, thus improving assessment acceptability. Two random square wave sequences and two maximum pressure settings (80 and 150 mmHg) were used, corresponding to four manoeuvres that were conducted in random order after a baseline recording. The intermittent application of thigh cuffs resulted in an amplitude dependent increase in ABP (p = 0.001) and cerebral blood flow velocity (CBFV) variability (p = 0.026) compared to baseline. No statistically significant differences in mean heart rate or heart rate variability were observed (p = 0.108 and p = 0.350, respectively), suggesting that no significant sympathetic response was elicited. No significant differences in the CBFV step response were observed, suggesting no distortion of autoregulatory parameters resulted from the use of thigh cuffs. We conclude that pseudorandom binary sequences are an effective and safe alternative for increasing ABP variability. This new approach shows great promise as a tool for the robust assessment of CA.