Regulator of calcineurin 1 (RCAN1), a crucial endogenous regulator of calcineurin, is implicated in multiple important physiological and pathological processes. Aberrant expression of RCAN1 is commonly found in brains of patients with Down syndrome (DS) or Alzheimer’s disease (AD), accounting for impaired neurodevelopment in DS and neuronal degeneration in AD, respectively. However, the mechanism of RCAN1 in brain development and neurodegeneration remains unclear. FBXW7 functions as vital factor in neurodevelopment and neurodegeneration via mediating proteasomal degradation of its substrates. Deficiency of FBXW7 contributes to impaired neurodevelopment and accelerating neurodegeneration. Here, we show that increased RCAN1 reduces the level of β isoform of FBXW7 (FBXW7β). RCAN1 inhibits FBXW7β transcription in a calcineurin dependent manner. Potential NFAT binding sites are identified within the promoter of FBXW7β, and NFAT is also demonstrated to activate the promoter activity of FBXW7β. In summary, our work implies that RCAN1 can regulate FBXW7β expression by inhibiting FBXW7β transcription via calcineurin/NFAT signaling pathway. It could provide more understanding on the mechanism of FBXW7 regulation and suggest a potential mechanism on functional implication of RCAN1 with impaired brain function in some neurodevelopmental and neurodegenerative diseases.