In this study, we demonstrate for the first time the dual roles of Tocopheryl Polyethylene Glycol 1000 Succinate (TPGS) based microemulsion (ME) for tacrolimus (TAC) to enhance TAC percutaneous delivery and anti-psoriatic efficacy. The ME formulation was developed and optimized based on pseudo-ternary phase diagrams combined with in vitro permeation. The result of Fourier transform infrared spectroscopy (FTIR) demonstrated that TAC was completely solubilized in the TPGS-ME. In vitro permeation studies showed that TPGS-ME enhanced TAC permeation through and into the skin, and the enhanced deposition of TAC in the normal or psoriatic skin was further confirmed in vivo. The cellular uptake performed with HaCaT cells presented more pronounced uptake of TPGS-ME. Topical TAC-TPGS-ME treated imiquimod-induced psoriasis in mice more efficaciously than the commercial formulation of TAC (Protopic®), which is consistent with the enhanced TAC levels by TAC-TPGS-ME in the psoriatic skin. Haematoxylin and Eosin (HE) staining revealed that TAC-TPGS-ME significantly diminished the severity of the psoriasis-like skin inflammation. Moreover, TPGS-ME vehicle exhibited a moderate anti-inflammatory activity, which indicated that TPGS acted as a potential adjuvant in the TAC anti-psoriasis process, and the synergism was identified in anti-proliferation against HaCaT cells. The colloidal nano-carrier combined ME with TPGS is a potential approach for percutaneous delivery of TAC, which exploited both virtues of ME and TPGS to obtain the synergetic effects of enhanced permeability and anti-psoriatic efficacy.