Thirty-five studies were included enrolling 353 individuals (16 women; 4.5%). Twenty-seven unique medications were tested. The average age of participants across studies was <30 years, and only one study included a clinical population. Under heat stress, there was moderate quality evidence that drugs with high anticholinergic properties increased core temperature at air temperatures ≥30°C (+0.42°C; 95% CI 0.04, 0.79°C; p = 0.03) alongside reduced sweating, although evidence is limited to the drug atropine. Similarly, non-selective beta-blockers (+0.11°C; 95% CI 0.02, 0.19°C; p = 0.02), adrenaline (+0.41°C; 95% CI 0.21, 0.61°C) and anti-Parkinson’s agents (+0.13°C; 95% CI 0.07, 0.19°C; p = 0.02) elevated core temperature. Antidepressants, diuretics, or drugs with weak anticholinergic effects did not alter core temperature responses. Current evidence supports strong anticholinergics, non-selective beta-blockers, adrenaline, and anti-Parkinson’s agents impairing thermoregulation during heat stress. No evidence indicated thermoregulation is impacted by other WHO-listed medications. Evidence is predominantly limited to healthy young men, with short heat stress exposures. Studies over longer durations, in women, older adults and those with chronic diseases are required to better inform the pharmaceutical management of patients during hot weather.