To overcome the unfavorable effects of the hydrophobicity of drugs and cancer resistance, mesoporous NiS2 nanospheres (mNiS2 NSs) have been successfully developed here to package hydrophobic camptothecin (CPT) and realize the synergistic photothermal-chemotherapy of cancer. The mNiS2 NSs which were prepared through a facile solvothermal method here exhibited not only considerable near-infrared (NIR) absorption and good photothermal conversion efficiency as high as 44.6%, but also achieved a NIR light induced CPT release property which were both beneficial for improving the cancer cell-killing efficacy. After a short period of NIR light illumination, a significant intensified cell killing efficacy was observed when 4T1 or HepG2 cancer cells were incubated with CPT@mNiS2 NSs. Thus, mNiS2 NSs have been demonstrated here to have potential as a novel NIR light-responsive hydrophobic drug delivery nanoplatform for realizing synergistic cancer treatment.