Paclitaxel (PTX) functions in various solid tumors such as 4T1, SKOV-3, B16F10 by stabilizing microtubule polymers to prevent their disassembly. However, it’s effectiveness in B16F10 tumor cells is reported to be limited by over expressed P-glycoprotein (P-gp), decreasing cellular accumulation of PTX in tumor cells. To overcome P-gp-mediated therapeutic limitation, We combined PTX(2.5 mg/kg) loaded mesoporous silica nanoparticles (SMB7DPP-PTX) with curcumin(CUR) 20 mg/kg, and D-α-tocopheryl polyethylene glycol 1000 succinate (TPGS) 60mg/kg [SDPCT] as P-gp modulators. [SDPCT] were subcutaneously administrated to B16F10 tumor bearing C57BL/C mice twice-daily cycle for 7 days and the therapeutic efficacy of [SDPCT] was compared against the therapeutic results from SMB7DPP-PTX with CUR [SDPC], and PTX with CUR [PC]. [SDPCT] group showed significant reduction in tumor size compared with [SDPC] and [PC] groups. And [SDPCT] group also showed 7.2-fold increased PTX accumulation in tumor tissue compared to [PC]. In vivo MTT assay showed 32 and 23% increased cell cytotoxicity when TPGS and CUR, respectively, were added to B16F10 cells combined with PTX treatment. 5 and 4-fold increased PTX uptake were also observed in B16F10 cells when TPGS and CUR, respectively, were treated with PTX. Taken these results together, TPGS and CUR effectively inhibited P-gp-mediated PTX efflux in B16F10 and increased PTX accumulation in tumor tissue without weight loss compared with control group. In conclusion, PTX nanoparticle complex combined with P-gp inhibitor such as curcumin and TPGS exhibited promising chemotherapeutic potential without significant body weight loss and non-target tissue toxicity.