Despite sparse systematic evidence, current exercise heat safety recommendations suggest that antihistamines blunt sweating and increase the risk for heat-related injury during exertional heat stress. The primary purpose of the present study was to examine whether diphenhydramine hydrochloride (DPH), a first-generation antihistamine, effects the sweating, core temperature, and heart rate response during exertional heat stress using a double-blind randomized crossover design. On two occasions separated by >48 h, 20 healthy adults (10 females, 23 ± 3 y, BSA: 1.9 ± 0.2 m2, BMI: 23.7 ± 2.2 kg·m-2) orally consumed either 50 mg of DPH or placebo (PLA), and then rested for 2 h in a climate-controlled room maintained at 30 °C and 35%RH (Heat Index of ~29 °C), followed by a 60-minute fixed-heat production treadmill walk (6.3 ± 1.0 W·kg-1). Whole-body sweat loss (WBSL), local sweat rate (LSR), rectal temperature (Trec), and heart rate (HR) were measured. WBSL was not different between conditions (PLA: 406 ± 78 g; DPH: 396 ± 75 g, P = 0.26, treatment effect: -10 g 95%CI [-28, 8]). No differences were observed for the onset for sweating (PLA: 13.5 ± 2.4 min; DPH: 13.3 ± 2.7 mins, P = 0.79), and steady-state LSR (PLA: 0.83 ± 0.26 mg·cm-2·min-1; DPH: 0.82 ± 0.27 mg·cm-2·min-1, P = 0.99). No difference in baseline Trec was observed (PLA: 37.09 ± 0.35 °C, DPH: 37.13 ± 0.33 °C, P = 0.68), and the 60-min ΔTrec was not different (P = 0.99) between PLA (0.83 ± 0.29 °C) and DPH (0.81 ± 0.30 °C). HR was similar at baseline (PLA: 86 ± 13 BPM, DPH: 84 ± 11 BPM, P = 0.30) and end-exercise (PLA: 134 ± 28 BPM, DPH: 132 ± 26BPM, P = 0.90). 50 mg of DPH does not modify the sweating, core temperature, and heart rate response during exertional heat stress in young healthy adults.