This study aimed to examine the exercise-induced heart rate response (HRR) and heart rate variability (HRV) in subjects caused by inhaling smoke from tobacco cigarettes (TC) and aerosolized vapor from electronic nicotine dispensing systems (ENDS) (commonly referred to as e-cigarettes (EC)). A randomized crossover study recruited 24 young adult male smokers with an average age of 23 years and with a smoking habit of at least two years. Heart rate response was recorded after a maximal multistage shuttle 20 m run test (MMST) under three different levels of nicotine: Control 0 mg nicotine of EC (C), 3 mg nicotine of EC (3EC), and 3 mg nicotine of TC (3TC). HRV was evaluated based on the beat-to-beat time interval during the running test. The results showed no statistically significant differences in the run time to exhaustion under the three conditions (C: 398 ± 151 s; 3EC: 399 ± 160 s; 3TC: 381 ± 150 s). Exercise-induced HRR was significantly attenuated under the TC condition (p < 0.05). Intriguingly, the HRV standard deviation of normal-to-normal intervals (SDNN) during exercise significantly increased under 3EC and 3TC. The results showed that a significant acute autonomic cardiac modulation during exercise is induced by an acute episode of EC and TC smoking.