Nanocarriers with strong tumor cell targeting ability have been expected to overcome limitations of cancer chemotherapy. Herein, cell membrane mimetic micelles were prepared from a random copolymer (PMNCF) containing cell membrane phosphorylcholine zwitterion, cholesterol, and tumor cell targeting folic acid (FA) at the side chain ends. Surface orientation of the FA ligand was optimized during PMNCF micelle preparation by controlling solvent solubility for FA. The out-oriented ligands on the micelles were immobilized by the strongly associated hydration layer around the closely packed phosphorylcholine zwitterions. The doxorubicin (DOX) loaded PMNCF micelles were demonstrated to reduce normal cell toxicity to less than 20%. More significantly, HeLa and MCF-7 tumor cell killing efficacy of the optimized formulation was enhanced to 160% compared with that of free DOX. The excellent performances of the drug loaded PMNCF micelles on both tumor cell killing and normal cell toxicity reducing efficacies reveal great potential for developing advanced drug delivery system.