The sigma-1 receptor is an important new therapeutic drug target for Alzheimer’s disease (AD). SOMCL-668 is a novel selective and potent sigma-1 receptor allosteric modulator, but its effect on AD is unknown. The present study found that SOMCL-668 is neuroprotective in AD in vitro and in vivo. SOMCL-668 concentration-dependently promoted the survival of PC12 cells against the toxicity of Aβ-1-42 induced ROS accumulation, caspase activation, LDH release, and apoptosis. The mechanical study showed that SOMCL-668 stimulated the phosphorylation of Raf, ERK, and CREB in a time and concentration-dependent manner, while the inhibition of the ERK pathway by PD98059 or ERK knockout with Cristp-cas9 attenuated its protective effect. Further studies with the sigma-1 receptor inhibitors/activators and the sigma-1 receptor knockout indicated that the sigma-1 receptor is essential for the effect of SOMCL-668. These results demonstrated that the neuronal protective effect of SOMCL-668 is mediated by the sigma-1 receptor/ERK/CREB pathway in PC12 cells. Similar results were obtained in SY5Y and primary cortical culture neurons. In 3xTg-AD mice, SOMCL-668 improved the learning and memory deficits, inhibited neuronal apoptosis and oxidative stress, and reduced Aβ deposition and tau protein phosphorylation by the ERK/CREB pathway. These results demonstrated that SOMCL-668 is neuronal protective in AD and its effect is mediated by the sigma-1 receptor/ERK/CREB pathway in vitro and in vivo. Our findings support that SOMCL-668 is a potential drug for the prevention and treatment of Alzheimer’s disease.