Background TGFB‐induced factor homeobox 2 (TGIF2) has been reported to exert essential functions in brain development. This study aimed to elucidate the correlation of TGIF2 with autism, a neurodevelopmental condition which presents with severe communication problems. Methods An autism‐related gene expression dataset GSE36315 was used to analyze aberrantly expressed genes in autistic brain tissues. Maternal mice were treated with valproate (VPA), and their offspring were selected as model mice with autism. The functions of TGIF2 in autism‐like symptoms in mice were examined by behavioral tests and histological examination of their hippocampal tissues. Mouse hippocampal neurons were extracted for in vitro studies. A gene set enrichment analysis was performed to analyze the signaling pathways involved, and the upstream factors influencing TGIF2 expression were explored in the ENCODE database and validated by ChIP‐qPCR assays. Results TGIF2 was poorly expressed in autistic patients in the GSE36315 dataset as well as in the temporal cortex tissues of autistic mice. Adenovirus‐mediated overexpression of TGIF2 suppressed autism‐like symptoms and neuronal apoptosis in autistic mice. TGIF2 activated the Wnt/β‐catenin signaling pathway. TGIF2 could be regulated by monomethylation of histone H3 Lys4 (H3K4me1). The histone demethylase LSD1 was highly expressed in the tissues of autistic mice and bound to TGIF2 promoter, which was possibly responsible for TGIF2 downregulation. Conclusion This research suggests that the downregulation of TGIF2, possibly regulated by LSD1/H3K4me1, is correlated with neuronal apoptosis and development of autism in mice through the inactivation of the Wnt/β‐catenin pathway.