Heat stroke often leads to multiple organ dysfunction syndrome (MODS) with a neurological morbidity of 30%. Current studies suggested that pathophysiological responses to heat stroke may be due to a systemic inflammatory response syndrome and a series of peptidergic nerve reactions. The mechanisms underlying the high neurological morbidity in heat stroke have remained largely elusive. In recent years, calcitonin gene-related peptide (CGRP) has been considered to have a positive role in central nervous system injury. The present study investigated the influence of CGRP on brain injury induced by heat stroke. A rat model of heat stroke was established in a pre-warmed artificial climate chamber with a temperature of 35.5±0.5°C and a relative humidity of 60±5%. The rectal core temperature (Tc) was monitored. Heat stress was halted at a Tc of no more than 41°C A bolus injection of CGRP was administered to each rat in the HS+CGRP group and a bolus injection of CGRP8-37 was administered to each rat in the HS+CGRP8-37 group after heat stress. After 2 h, electroencephalograms were recorded and the pathological morphology of brain tissue as well as brain cell apoptosis and caspase-3 protein levels in the brain were measured. The EEG of rats in the HS+CGRP group was characterized by a short- to long-term α-wave and low-voltage β-waves as well as a large amount of intermittent δ- and θ-waves. Compared with the HS group, the θ-wave decreased and the α-wave increased significantly (P<0.05). Slight pathological damage of nerve cells appeared in the HS+CGRP group. Greater damage was observed in HS+CGRP8-37 group with neural cell shrinkage, volume reduction, nuclear pyknosis, disappearance of part of the nuclear membrane and cell necrosis. In the HS+CGRP group, apoptotic cells and caspase-3 protein in the brain were significantly decreased when compared with those in the HS group (P<0.05), while they were significantly increased in the HS+CGRP8-37 group (P<0.05 vs. HS group). The results of the present study reflected that CGRP has a protective effect on early-stage brain injury induced by heat stroke in rats.