The effects of quinacrine (QA) on heat-induced neuronal injury have been explored, with the intention of understanding the mechanisms of QA protection. Primary cultivated striatum neurons from newborn rats were treated with QA 1 h before heat treatment at 43 °C which lasted for another 1 h, and necrosis and apoptosis were detected by Annexin-V-FITC and propidium iodide (PI) double staining. Neuronal apoptosis was determined using terminal deoxynucleotidyl transferase-mediated biotinylated UTP nick end labeling (TUNEL) techniques. Cell membrane fluidity, activity of cytosolic phospholipase A2 (cPLA2) and the level of arachidonic acid (AA) were also examined. Membrane surface ultrastructure of striatum neurons was investigated by atomic force microscopy (AFM). Results showed that heat treatment induced great striatum neurons death, with many dying neurons undergoing necrosis rather than apoptosis. QA alone had little effect on the survival of striatum neurons, while QA pretreatment before heat treatment decreased necrosis. Heat treatment also resulted in decreased membrane fluidity and increased cPLA2 activity as well as arachidonic acid level; these effects were reversed by QA pretreatment. QA pretreatment also significantly prevented damage to the membrane surface ultrastructure of heat-treated neurons. These results suggest that QA protects striatum neurons against heat-induced neuronal necrosis, and also demonstrate that inhibition of cPLA2 activity and stabilization of membranes may contribute to protective effect of quinacrine.