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In this study, tacrolimus microemulsion-in situ gel（TC-EM-ISG） was prepared by cold method. This drug delivery system is to uniformly disperse TC-loaded EM, which ensures better solubility and higher stability of TC, as well as better medication compliance, in the in-situ gel matrix composed of poloxamer 407（F127） and poloxamer 188（F68） as thermosensitive gel media to improve residence time of TC in the cornea, its bioavailability and medication compliance. In this study, TC-EM-ISG formulation is optimized using its gelatinization temperature（Tg~1 and Tg~2） before and after dilution of simulated tear fluid（STF） as a composite index and orthogonal experiment design: 14% poloxamer 407（F127） and 2% poloxamer 188（F68） was the best gel medium composition for 0.1% TC-EM-ISG. In this study, appearance, particle size distribution, morphology, gelatinization temperature, rheological properties and in vitro release characteristics of TC-EM-ISG were investigated: it appeared clear and transparent, average gelatinization temperatures inside and outside the eye were respectively（27.1 ± 0.93）oC and（33.9 ± 0.45）oC（n = 3） and average particle size distribution was（18.70 ± 0.96） nm（n = 3）. Emulsion droplets in elliptic shapes were evenly distributed in ISG before and after gelatinization. Its good shear shinning of pseudoplastic fluid properties under physiological conditions was applicable for ophthalmic use. In vitro dissolution and release tests showed that its releasing characteristics followed zero-order kinetics. In vivo residence time of TC-EM and TC-EM-ISG were（15.63 ± 1.54） min and（22.67 ± 1.54） min respectively in comparison with（15.67 ± 3.51） min for tacrolimus suspension eye drops（TC-SP） as control. Irritations of TC-SP, TC-EM and TC-EM-ISG after single and multiple dose administrations were evaluated against normal saline as control by intra-individual self-control method with Draize test criteria. All scores averaged below 3, which indicated non-irritating. This study showed it was feasible to prepare TC-EM-ISG from TC-EM by a simple process with controllable quality, good stability and low irritations. It is expected to be a good ophthalmic drug delivery system for hydrophobic drug substances due to its steady and slow releasing of drug substances in comparison with TC-SP eye drops.