While topical corticosteroid (TCS) treatment is widely used for many skin diseases, it can trigger adverse side effects, and some of such effects can last for a long time after stopping the treatment. However, molecular changes induced by TCS treatment remain largely unexplored, although transient changes in histology and some major ECM components have been documented. Here, we investigated transcriptomic and proteomic changes induced by fluocinolone acetonide (FA) treatment in the mouse skin by conducting RNA-Seq and quantitative proteomics. Chronic FA treatment affected the expression of 4229 genes, where downregulated genes were involved in cell-cycle progression and ECM organization, and upregulated genes were involved in lipid metabolism. The effects of FA on transcriptome and histology of the skin largely returned to normal by two weeks after the treatment. Only a fraction of transcriptomic changes were reflected by proteomic changes, and the expression of 46 proteins was affected one day after chronic FA treatment. A comparable number of proteins were differentially expressed between control and FA-treated skin samples even at 15 and 30 days after stopping chronic FA treatment. Interestingly, proteins affected during and after chronic FA treatment were largely different. Our results provide fundamental information of molecular changes induced by FA treatment in the skin.