Background: Multidrug resistance (MDR) is one of the primary causes of tumor chemotherapy failure. Therefore, it is essential to uncover new drug treatment protocols. In the current study, employing chitosan (CS) and sodium tripolyphosphate (TPP) as carriers and cross-linking agents, the proanthocyanidins (PHL)/poly (lactic-co-glycolic acid) (PLGA) were encapsulated by emulsion solvent evaporation, through which the cationic CS-PLGA-PHL nanosystem was obtained. The effectiveness of CS-PLGAPHL on the invasion and migration of human oral squamous cell carcinoma cells was discussed, as were their potential mechanisms. Materials and Methods: A CS-PLGA-PHL nanosystem was constructed by emulsion-solvent evaporation. The size distribution, dispersion, and morphology were characterised by the laser particle size analyser and transmission electron microscope. Human oral squamous cell carcinoma drug-resistant cell lines SCC131/R and SCC-15/DDP were cultured in vitro. The two cell types were induced at different concentrations by CS-PLGA-PHL, after which a CCK-8 experiment was performed to determine the effect of CS-PLGA-PHL on the proliferation of the two cell lines. The 50% inhibitory concentration (IC50) of CS-LGA-PHL was calculated at different time points. The transwell chamber experiment was performed to identify the effects of CS-PLGA- PHL on the migration and invasion of OSCC cells. The expression levels of MMP-2 and MMP-9 were detected by Western blot and q-PCR. Results: CS-PLGA-PHL is well dispersed. The PDI appeared to be lowest when the mass ratio of chitosan to PLGA equaled 1:15. CS-PLGA-PHL exhibited a marked effect in inhibiting the proliferation of SCC131/R and SCC-15/DDP as well as the invasion and migration. CS-PLGA-PHL was able to downregulate the expression of MMP-2 and MMP-9 genes and proteins significantly in drug-resistant cell lines. Conclusion: CS- PLGA-PHL for oral squamous cell carcinoma has been successfully prepared to exert significant inhibition on the proliferation, invasion, and migration of OSCC cells. The mechanism involved was possibly related to the down-regulation of MMP-2 and MMP-9 expression by CS-PLGA-PHL.