Background: Breast cancer (BC) has the highest global prevalence among all malignancies in women and the second highest prevalence in the overall population. Paclitaxel (PTX), a tricyclic diterpenoid, is effective against BC. However, its poor solubility in water and the allergenicity of its dissolution medium limited its clinical application. Methods: In this work, we established a multifunctional graphene oxide (GO) tumor-targeting drug delivery system using nanosized graphene oxide (nGO) modified with D-tocopherol polyethylene glycol succinate (TPGS) and arginine-glycine-aspartic acid (RGD) for PTX loading. Results: The obtained RGD-TPGS-nGO-PTX was 310.20±19.86 nm in size; the polydispersity index (PDI) and zeta potential were 0.21±0.020 and -23.42 mV, respectively. The mean drug loading capacity of RGD-TPGS-nGO-PTX was 48.78%. RGD-TPGS-nGO-PTX showed satisfactory biocompatibility and biosafety and had no significant toxic effects on zebrafish embryos. Importantly, it exerted excellent cytotoxicity against MDA-MB-231 cells, reversed multi-drug resistance (MDR) in MCF-7/ADR cells, and showed significant anti-tumor efficacy in tumor-bearing nude mice. Conclusion: These findings strongly suggested that the multifunctional GO tumor-targeting drug delivery system RGD-TPGS-nGO-PTX could be used in clinical settings to improve PTX delivery, reverse MDR and increase the therapeutic efficacy of BC treatment.