AIM: To investigate the regulatory effects and mechanisms of glycyrrhizin on morphine-induced neurotoxicity. METHODS: A neurotoxicity model was established by intracerebroventricular injection of morphine. Glycyrrhizin was administered intraperitoneally for 5 and 10 days. Pathological observation, protein immunoblotting, cell viability, apoptosis, and primary neuron differentiation were assessed. RESULTS: After morphine treatment, neuronal loss, decreased cell viability, increased apoptosis, axonal breakage, and cell shrinkage were observed in cortical tissue. Glycyrrhizin administration significantly improved cell viability, and axonal, dendritic, and cell body structures gradually became intact, with reduced apoptosis. The phosphorylation levels of protein Akt at position 473 and PKA at position 197 decreased, while autophagy-related proteins Beclin and LC3B1/2 remained unchanged. CONCLUSION: Glycyrrhizin significantly inhibits morphine-induced neuronal differentiation suppression and neuronal apoptosis, which may be mediated through the synergistic effects of glycyrrhizin and morphine on the Akt pathway.