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Background: Prenatal exposure to adverse factors can cause congenital heart defects. Ketamine, a widely used anesthetic drug, produces several adverse reactions such as tachycardia, hypertension, and laryngospasm, especially in pediatric patients. This study aimed to detect the effects of ketamine exposure during pregnancy on the cardiogenesis of mouse offspring and the potential mechanisms. Methods: In this study, ketamine at an addictive dose (5 mg/kg) was administered to mice during early gestation to explore the epigenetic mechanism of its causing cardiac dysplasia. The cardiac morphology of the mouse offspring was observed through hematoxylin–eosin staining and transmission electron microscopy. The heart function of one‐month‐old neonates was detected by echocardiography. The expression of cardiomyogenesis‐related genes was detected by western blot and RT‐qPCR. The acetylation level of histone H3K9 at the Mlc2 promoter and its deacetylase level and activity were detected by CHIP‐qPCR, RT‐qPCR, and ELISA, respectively. Results: Our data revealed that ketamine exposure during pregnancy could cause cardiac enlargement, myocardial sarcomere disorganization, and decreased cardiac contractile function in mouse offspring. Moreover, ketamine reduced the expression of Myh6, Myh7, Mlc2, Mef2c, and cTnI. The histone H3K9 acetylation level at the Mlc2 promoter was down‐regulated by increasing the histone deacetylase activity and HDAC3 level upon ketamine administration. Conclusions: Our work indicates that H3K9 acetylation is a vital player in cardiac dysplasia in offspring caused by prenatal ketamine exposure and HDAC3 is a key regulatory factor. [ABSTRACT FROM AUTHOR]