Purpose We aimed to analyse the acute effects of set configuration on cardiac parasympathetic modulation and blood pressure (BP) after a whole-body resistance training (RT) session. Methods Thirty-two participants (23 men and 9 women) performed one control (CON) and two RT sessions differing in the set configuration but with the same intensity (15RM load), volume (200 repetitions) and total resting time (360 s between sets for each exercise and 3 min between exercises): a long set configuration (LSC: 4 sets of 10 repetitions with 2 resting minutes) and a short set configuration session (SSC, 8 sets of 5 repetitions with 51 resting seconds). Heart rate variability, baroreflex sensitivity, the low frequency of systolic blood pressure oscillations (LFSBP), BP and lactatemia were evaluated before and after the sessions and mechanical performance was evaluated during exercise. Results LSC induced greater reductions on cardiac parasympathetic modulation versus SSC after the session and the CON (p < 0.001 top = 0.024). However, no LFSBP and BP significant changes were observed. Furthermore, LSC caused a higher lactate production (p < 0.001) and velocity loss (p <= 0.001) in comparison with SSC. Conclusion These findings suggest that SSC attenuates the reduction of cardiac parasympathetic modulation after a whole-body RT, improving the mechanical performance and decreasing the glycolytic involvement, without alterations regarding vascular tone and BP.