Poly(lactic acid) (PLA) nanoparticles (NPs) are the most promising polymer NPs for drug delivery and targeting. However, they are easily recognized as a foreign body and rapidly cleared from the body by the mononuclear phagocyte system. Cell membrane mimetic random copolymers, bearing both zwitterionic phosphorylcholine groups and hydrophobic butyl side chains (PMB) and additional cross-linkable trimethoxysilylpropyl side chains (PMBT), were synthesized and coated on PLA NPs. Effects of the zwitterionic copolymer coatings on the NP size distribution, dispersion stability, and drug release behavior were investigated. Furthermore, the effect of the coatings on phagocytosis was also investigated. Compared with conventional polyvinyl alcohol coating, the cell membrane mimetic copolymer coatings decreased the size and increased the stability of the PLA NPs aqueous dispersions. More importantly, doxorubicin (DOX) release was well controlled and NPs phagocytosis by mouse peritoneal macrophage was decreased to one-third when the nanoparticles were coated with PMBT. This simple and effective zwitterionic polymer coating strategy may serve as a new route to design and optimize long-circulating intravenously injectable nanoparticle drug carriers.