The aim of the present study is to evaluate the effect of polyethylene glycol (PEG) chain organization on various physicochemical aspects of drug delivery from poly(D, L-lactide) (PLA) based nanoparticles (NPs). To reach that goal, two different pegylated polymers of poly(D, L-lactide) (PLA) were synthesized. Polymers used in this study are grafted ones in which PEG was grafted on PLA backbone at 7% (mol/mol of lactic acid monomer), PEG7%-g-PLA, and multiblock copolymer of both PLA and PEG, (PLA-PEG-PLA)n with nearly similar PEG insertion ratio and the same PEG chain length. Blank and ibuprofen-loaded NPs were prepared from both polymers and their properties were compared to PLA homopolymer NPs as a control. Encapsulation efficiency of ibuprofen was found to be approximately 25% for (PLA-PEG-PLA)n NPs and approximately 80% for PEG7%-g-PLA NPs. (PLA-PEG-PLA)n NPs either blank or loaded showed larger hydrodynamic diameter (approximately 200 nm) than PEG7%-g-PLA NPs (approximately 135 nm). A significant difference was observed in the amount of PVA associated with the surface of both NPs where 3.6% and 0.4% (wt/wt) were found on the surface of PEG7%-g-PLA and (PLA-PEG-PLA)n NPs, respectively. No observed difference in zeta potential values for both NPs formulations was found. DSC showed the existence of the drug in a crystalline state inside NPs matrix irrespective of the type of polymer used with either shifting or/and broadening of the drug melting endotherm. Both AFM phase imaging and XPS studies revealed the possibility of existence of more PEG chains at the surface of grafted polymer NPs than (PLA-PEG-PLA)n during NPs formation. The in vitro release behavior showed that (PLA-PEG-PLA)n NPs exhibited faster release rates than PEG7%-g-PLA NPs. The physicochemical differences obtained between both polymers were probably due to different chain organization during NPs formulation. Such pegylated NPs made from these two different polymers might find many applications, being able to convert poorly soluble, poorly absorbed substances into promising drugs, improving their therapeutic performance, and helping them reach adequately their target area. Our results suggest that the properties of pegylated PLA-based NPs can be tuned by proper selection of both polymer composition and polymer architecture.