Autism is a complex neurodevelopmental disease that may be caused by genetic and environmental factors, that are incompletely understood. Overactivation of dopaminergic receptors can lead to autistic-like behavior. β-arrestin2 (Arrb2) is a scaffolding protein of the arrestin family, which function as cytosolic multifunctional adapter proteins that activate cell signal transduction and mediate the signal termination and endocytosis of G-protein-coupled receptors (GPCRs) complexes. In this study, we established an Arrb2 knockout (Arrb2) mouse to explore the biological function of Arrb2 in autistic-like behavior caused by abnormality in the dopaminergic system. We found that Arrb2 mice did not exhibit the autistic-like behavior normally induced by SKF38393, an agonist of the dopamine receptor 1 (D1R). Compared with wild-type (WT) untreated mice, the SKF38393-treated WT mice and Arrb2 mice, with or without SKF38393 treatment, showed abnormalities on electroencephalography (EEG) and increased stimulation of the phosphorylated form of extracellular signal-regulated kinase (p-ERK) via the PKA/Rap1/B-Raf/MEK pathway. These results demonstrated that Arrb2 regulated the dopaminergic system through the ERK signaling pathway in the occurrence and development of autism, and that targeted deletion of Arrb2 impeded the development of autistic-like behavior.