Upconversion nanoparticles (UCNPs) have attracted much attention as potential photosensitizer carriers for photodynamic therapy (PDT) in deep tissues. In this study, hydrophilic UCNPs were prepared by coating amphiphilic chitosan (N-succinyl-N′-octyl chitosan, SOC) on the surface of hydrophobic oleic acid-capped NaYF 4 UCNPs (OA-UCNPs). Water-insoluble photosensitizer zinc(ii) phthalocyanine (ZnPc) was loaded into the SOC-coated UCNPs (SOC-UCNPs) via hydrophobic interactions to form a novel drug delivery system for in vivo deep tissue PDT triggered by near-infrared (NIR) light. The ZnPc-loaded SOC-UCNPs exhibited good dispersibility, excellent optical properties and good photostability. Under NIR light irradiation, the measurement of singlet oxygen production indicated that ZnPc effectively generated singlet oxygen induced by the emission from the UCNPs. Cell viability assays showed the low cytotoxicity of the UCNPs after surface modification. In vitro and in vivo therapeutic investigation evidenced the prominent PDT effects of ZnPc-loaded SOC-UCNPs upon NIR light irradiation. Furthermore, NIR imaging of ICG derivative-loaded SOC-UCNPs after intra-tumoral injection indicated the high retention of SOC-UCNPs only in the tumor site. Histological examination confirmed the negligible toxicity of ZnPc-loaded SOC-UCNPs on other organs. All the results demonstrate the promising potential of using SOC-UCNPs as new photosensitizer carriers for PDT of cancer and other diseases in deep tissues.