Photodynamic therapy (PDT) as a noninvasive technique is widely used to treat cancer diseases due to its low side effects. PDT based on upconversion nanoparticles (UCNPs) improved tissue penetration and photo-stability. However, traditional photosensitizers and UCNPs were difficult to incorporate, which limited the circulation of the UCNPs in blood and decreased the PDT effect. Herein, we designed NaErF@ZnO UCNPs for potential application in thyroid tumor cell PDT. With ZnO coated on NaErF, the blue (415 nm), green (525 nm/545 nm) and red (661 nm) upconversion luminescence enhanced compared with that of NaErF core nanoparticles. Particularly, the generation of UV upconversion emission by NaErF sensitized ZnO, which catalyzed HO and O to produce ROS reactive oxygen species (ROS) to induce papillary thyroid carcinoma (PTC) cell lines BHP 5-16. With 1000 μg mL of NaErF@ZnO UCNPs, the viability of BHP 5-16 cells decreased to about 41% as measured by CCK8 assay with 980 nm NIR irradiation. Moreover, it was confirmed that NaErF@ZnO UCNPs had low toxicity for BHP 5-16 cells. All these results indicated that NaErF@ZnO upconversion nanoparticles were an excellent platform for PDT treatment.