Various mutations of the SH3 and multiple ankyrin repeat domains 3 (SHANK3) gene, encoding excitatory postsynaptic core scaffolds, are associated with neurodevelopmental and neuropsychiatric disorders. Thus far, synaptic abnormalities in multiple brain regions, including the hippocampus, prefrontal cortex, striatum, and ventral tegmental area, have been investigated in several lines of Shank3 mutant mice. However, even with some reports showing loss and gain of body weight in Shank3 knock-out and overexpressing transgenic (TG) mice, respectively, potential functions of Shank3 in the hypothalamus, a brain region critically involved in energy intake and expenditure, are unknown. To address this issue, we first characterized endogenous Shank3 mRNA and protein expression in the hypothalamus of adult wild-type mice. Then, we performed transcriptome analysis (RNA-sequencing) in the hypothalamus of adult Shank3 TG mice which mildly overexpress Shank3 proteins. By comparing the 174 differentially expressed genes of the hypothalamus with those of previously reported striatum and medial prefrontal cortex (mPFC) in Shank3 TG mice, we found that 159 were hypothalamus-specific while only 15 were shared with either striatum or mPFC. Furthermore, from Gene Set Enrichment Analysis of the RNA-sequencing analysis, we found that ribosome-related genes were enriched especially in the up-regulated genes of Shank3 TG hypothalamus, which is opposite to the analyses on Shank3 TG striatum and mPFC where ribosome-related genes were enriched in the down-regulated genes. Beyond showing endogenous Shank3 mRNA and protein expression in the hypothalamus, our results suggest unique molecular changes in the hypothalamus of Shank3 TG mice compared with the striatum and mPFC.