Sample entropy (SampEn) has been used to quantify the regularity or predictability of human gait signals. There are studies on the appropriate use of this measure for inter-stride spatio-temporal gait variables. However, the sensitivity of this measure to preprocessing of the signal and to variant values of template size (m), tolerance size (r), and sampling rate has not been studied when applied to “whole” gait signals. Whole gait signals are the entire time series data obtained from force or inertial sensors. This study systematically investigates the sensitivity of SampEn of the center of pressure displacement in the mediolateral direction (ML COP-D) to variant parameter values and two pre-processing methods. These two methods are filtering the high-frequency components and resampling the signals to have the same average number of data points per stride. The discriminatory ability of SampEn is studied by comparing treadmill walk only (WO) to dual-task (DT) condition. The results suggest that SampEn maintains the directional difference between two walking conditions across variant parameter values, showing a significant increase from WO to DT condition, especially when signals are low-pass filtered. Moreover, when gait speed is different between test conditions, signals should be low-pass filtered and resampled to have the same average number of data points per stride.