Objectives: This study aimed to investigate the regulatory impact of early swimming intervention on striatal metabolism in Shank3 gene knockout ASD model rats. Methods: Shank3 gene knockout exon 11–21 male 8-day-old SD rats were used as experimental subjects and randomly divided into the following three groups: a Shank3 knockout control group (KC), a wild-type control group (WC) from the same litter, and a Shank3 knockout swimming group (KS). The rats in the exercise group received early swimming intervention for 8 weeks starting at 8 days old. LC-MS metabolism was employed to detect the changes in metabolites in the striatum. Results: There were 17 differential metabolites (14 down-regulated) between the KC and WC groups, 19 differential metabolites (18 up-regulated) between the KS and KC groups, and 22 differential metabolites (18 up-regulated) between the KS and WC groups. Conclusions: The metabolism of striatum in Shank3 knockout ASD model rats is disrupted, involving metabolites related to synaptic morphology, and the Glu and GABAergic synapses are abnormal. Early swimming intervention regulated the striatal metabolome group of the ASD model rats, with differential metabolites primarily related to nerve development, synaptic membrane structure, and synaptic signal transduction.