Abstract Background Biodegradable polymers are commonly used as dermal fillers in plastic surgery. Among these, poly-L-lactic acid (PLLA) distinguishes itself owing to its good biocompatibility, degradability, and ability to act as a collagen stimulator. Objectives In this study, the differential behavior of PLLA microspheres with varying microscopic morphology and surface hydrophilicity was investigated both in vitro and in vivo. Methods The introduction of short hydrophilic polyethylene glycol (PEG) chains into the PLLA molecule was employed to modify the morphology and enhance the surface hydrophilicity of the microspheres. The morphology and physicochemical properties of the PLLA and PLLA-b-PEG microspheres were characterized. Irregular PLLA particles, PLLA and PLLA-b-PEG microspheres were implanted into the subcutaneous tissue of rabbit models, and at 4, 26 and 52 weeks after implantation, biopsy samples were collected for hematoxylin and eosin (H&E) and Masson's trichrome staining to evaluate differences in the tissue response between different implants. Results The results of in vitro research demonstrated that while the addition of short-chain hydrophilic PEG afforded a smoother surface for the microspheres, it had no significant effect on the molecular weight and degradation rate of PLLA. The histological examination revealed that the PLLA-b-PEG microspheres exhibited enhanced biocompatibility compared to the pure PLLA microspheres, while the irregular PLLA particles showed the highest inflammatory response among the three materials. Conclusions In this study, we found that the properties of PLLA were improved upon modification by short-chain PEG without reducing the collagen regeneration ability, thereby affording a better histocompatibility.