Lung cancer remains the leading cause of cancer associated deaths worldwide. Compared with traditional chemotherapy for non-small cell lung cancer (NSCLC), specific targeted therapies are better choices for advanced patients to improve their survival. In this study, we attempted to fabricate Nitroimidazoles (NI) and Hyaluronic acid (HA) co-decorated, cisplatin (DDP) loaded polymeric nanoparticles (PNPs) (NI/HA-DDP-PNPs) and lipid-polymer hybrid nanoparticles (LPNs) (NI/HA-DDP-LPNs) for the facilitated drug delivery at lung tumor regions (hypoxic regions). In vitro cytotoxicity and cellular uptake; In vivo anti-tumor activity and in vivo tissue biodistribution of PNPs and LPNs were evaluated and compared in lung carcinoma cells and xenograft. Hydrodynamic size of NI/HA-DDP-LPNs was 185.6 ± 4.7 nm, which is larger than that of NI/HA-DDP-PNPs (136.7 ± 3.5 nm). The zeta potential of NI/HA-DDP-PNPs (-31.2 ± 2.7 mV) was more negative than NI/HA-DDP-LPNs (-22.3 ± 2.1 mV). The peak plasma concentration (C_max) achieved from NI/HA-DDP-PNPs and NI/HA-DDP-LPNs was 35.2 ± 1.6 and 37.3 ± 1.7 μg/mL. The half-life (T_1/2) of NI/HA-DDP-PNPs and NI/HA-DDP-LPNs was 12.03 ± 0.75 and 11.78 ± 0.89 h. Area Under Curve (AUC) of NI/HA-DDP-PNPs and NI/HA-DDP-LPNs showed no significant difference while greater than other groups. NI/HA-DDP-LPNs exhibited excellent antitumor effect against drug-resistant human lung cancer A549/DDP cells in vitro and in vivo, better than that of NI/HA-DDP-PNPs. Considering that the low toxicity of NI/HA-DDP-LPNs and NI/HA-DDP-PNPs, NI/HA-DDP-LPNs could be a more promising system for lung cancer targeted therapy.