The clinical success of lipid–polymer hybrid nanoparticles (LPHNPs) for effective targeted drug delivery is still hindered by their rapid clearance from the bloodstream. In this work, a novel strategy for surface modification of LPHNPs with combined polyethylene glycol (PEG) and heparin (HEP) was developed to achieve a significant prolongation in blood circulation. All the LPHNPs formulated with a diameter of 100–200 nm were prepared by a modified w/o/w solvent diffusion/evaporation method and physicochemically characterized. The synergistic action of PEG and HEP was observed, as combinatorial modification significantly improved the surface hydrophilicity as well as the suspension stability of nanoparticles and tailored the surface charge close to neutrality, in comparison to LPHNPs surface-treated with PEG or HEP alone. In vitro and in vivo studies showed that the PEG/HEP coating significantly prohibited the macrophage uptake and extended the blood circulation of LPHNPs with concomitant reduced liver sequestration. The in vitro phagocytosis results using murine peritoneal macrophages showed 8.2-fold reduction compared to the control LPHNP group. The in vivo study in ICR mice showed PEG/HEP coating increased the blood circulation half-life of LPHNPs from 0.3 h to 72.6 h. Moreover, PEG/HEP LPHNPs exhibited dramatically reduced liver accumulation when compared to LPHNPs. These results demonstrated that PEG/HEP LPHNPs with optimized particle size, surface hydrophilicity and surface charge, have a promising potential as long-circulating drug delivery systems.