Folate receptor-targeted nanophotosensitizer (NaYF4:Yb,Tm@NaGdF4:Yb@TiO2 @PEI-PAA-FA) was prepared by coating TiO2 on the upconversion nanoparticles NaYF4:Yb,Tm@NaGdF4:Yb via a hydrolysis method, followed by modification with polyethyleneimine (PEI) and polyacrylic acid (PAA) and subsequent conjugation of folic acid (FA). XRD and TEM were used to characterize the crystal structure and morphology of the inorganic components of the nanophotosensitizer. FTIR and ξ potential were used to verify the binding of these organic components. Upconversion luminescence spectra of the samples were also measured. The decrease in the absorbance of 1,3-Diphenylisobenzofuran solution in the presence of the nanophotosensitizer under 980 nm near-infrared (NIR) laser irradiation indicated the singlet oxygen has been produced from the nanophotosensitizer. Besides, the photosensitizer has a doxorubicin (DOX) loading capacity, the maximum drug loading ratio was 50.8% and the encapsulation efficiency was 84.7%. The DOX release from the nanophotosensitizer was sensitive to the pH value of the buffer. As the DOX-loaded nanophotosensitizer was suspended in an acidic buffer of pH 5.0 and exposed to NIR laser irradiation, the cumulative release of DOX at 12 h was 38.1%, much higher than that obtained from a neutral buffer (pH 7.4), which was 10.4%. These results indicated the DOX-loaded and FA-coupled nanophotosensitizer may be a potential drug for synergistic inactivation of cancer cell by NIR-driven photodynamic therapeutic and chemotherapeutic modalities.