Multiple drug resistance, which leads to tumor recurrence and contributes to high mortality rates in ovarian cancer, is a significant issue that must be overcome for successful treatment. Within this study, we explored the efficacy of lipid-chitosan hybrid nanoparticles with NTD as an ABCB1 inhibitor and PTX as a chemotherapeutic agent in ABCB1 overexpressed ovarian cancer cells. Sensitive ovarian cancer cells acquired resistance by continuous paclitaxel treatment and confirmed by the resistance index and ABCB1 expression by qRT-PCR. PTX-NTD-loaded lipid-chitosan hybrid nanoparticles (N-PTX-LPHNPs) were synthesized via ionic gelation and characterized by the DLS method, in vitro release, encapsulation and loading efficiency, FT-IR and SEM. XTT, Rho-123 accumulation assay, and DCFH-DA staining were conducted to examine the drug resistance inhibition and anti-cancer activity of NTD and N-PTX-LPHNPs. Bioinformatics analyzes were performed to evaluate the ADME/T properties of NTD and the interaction between the PTX-NTD combination and ABCB1. NTD showed high binding affinity to ABCB1 and had cytotoxicity against ovarian cancer cells. Moreover, the PTX-NTD drug combination loaded nanoparticles increased PTX accumulation and intracellular ROS levels, enhanced anti-cancer activity, and overcame resistance to ovarian cancer. Our results highlight the NTD-PTX-loaded lipid-chitosan hybrid nanoparticles as a potential therapeutic for ABCB1 overexpressed ovarian cancer.