GGA (geranylgeranylacetone) may induce Hsp70 synthesis, thus contributing to the protective effects of GGA in several disease states. This study evaluated the protective effects of GGA against heat injury to rat and striatum neurons in terms of mechanisms. Rats were exposed to 41.5°C for 35 min to induce heatstroke; the protective effects of GGA were then evaluated by change in rectal temperature (Tre) during heat exposure and survival time after heatstroke. Primary cultured striatum neurons were incubated with GGA for 24h, and then heat-treated at 43°C for a further 1h. The viability, membrane surface ultrastructure and Hsp70 expression of striatum neurons were all observed. Furthermore, the effects of quercetin an inhibitor of Hsp70 synthesis were also investigated. Compared to the heatstroke group, GGA delayed Tre in reaching 42.1°C (P<0.05) and prolonged the survival time after heatstroke (P<0.01). The LDH releasing percentage decreased in GGA groups (P<0.05, P<0.01) compared to the heat-treatment group and increased in quercetin groups (P<0.05) compared to GGA group. Results from AFM showed that GGA protected membrane surface ultrastructure against heat injury. In addition, results from Western blot showed that GGA-induced Hsp70 expression of neurons both in normal and heat-treatment conditions (P<0.01, P<0.05) and quercetin inhibited GGA-induced Hsp70 expression (P<0.05). Therefore, GGA had protective effects against heat injury in striatum neurons and rat heatstroke. Quercetin inhibited GGA-induced Hsp70 expression and prevented GGA-protective effects, which indicated that this protection was dependent on the Hsp70 synthesis.