The neuroprotective impact of curcumin and the role of CREB-BDNF signaling in this way was evaluated in methamphetamine (METH)-induced neurodegeneration in rats. Sixty adult male rats were randomly split into 6 groups. While normal saline and 10 mg / kg METH were administered intraperitoneally in Groups 1 and 2, Groups 3, 4, 5 and 6 received METH (10 mg/kg) and Curcumin (10, 20, 40 and 80 mg/kg respectively) simultaneously. Morris Water Maze (MWM), oxidative hippocampal, antioxidant, inflammatory, apoptotic, and CREB and BDNF were assessed. We've found that METH disturbs learning and memory. Concurrent curcumin therapy (40 and 80 mg / kg) decreased cognitive disturbance caused by METH. Multiple parameters, such as lipid peroxidation, oxidized form of glutathione (GSSG), interleukin 1 beta (IL-1β), tumor necrosis factor alpha (TNF-α) and Bax, increased by METH therapy, although the reduced type of glutathione (GSH), Bcl-2, P-CREB and BDNF concentrations in the hippocampus decreased. Different doses of curcumin adversely attenuated METH-induced apoptosis, oxidative stress and inflammation, but enhanced concentrations of P-CREB and BDNF. Curcumin-caused neuroprotection against METH-induced neurodegeneration is conducted by P-CREB / BDNF signaling pathway activation.