Tacrolimus monohydrate (TAC) loaded core shell lipid polymer hybrid nanoparticle (CS-LPHNs) composed of polymer core (PLGA) surrounded by lipid shell (lecithin). DSPE-PEG2000 was used as stabilize the nanoparticles. TAC-CS-LPHNs were prepared by single step modified nanoprecipitation method. Field emission electron microscope and Transmission Electron Microscope reveals a spherical shape nano-sized particle coated with a lipid layer. The nanoparticles ranged in size from 82nm±0.2-195±0.143nm which increase with increase the polymer quantity. The entrapment efficiency also affected by the polymer quantity that ranges from 55±1.23%-76±1.93%. XRD and DSC studies show conversion of TAC from crystalline into amorphous when imbedded inside the CS-LPHNs and FTIR study shows no chemical interaction between TAC and other components. The Cytotoxicity study of TAC and TAC-CS-LPHNs show a decrease in cytotoxicity of loaded TAC (IC50=1.18067±0.045µg/ml) in compare with free TAC(IC50=0.697±0.02µg/ml). Finally, the uptake study shows complete internalization of nanoparticle by Vero cell and accumulation of nanoparticles inside nucleus and cytoplasm. The results suggested CSLPHNs is a good drug delivery system for TAC which is safe, effective and promising a better clinicals outcome.