Photodynamic therapy (PDT) is a noninvasive therapeutic technique. Upconversion nanoparticles (UCNPs) hold promise for photodynamic therapy (PDT). UCNPs with antistokes emission can improve the tissue penetration depth of PDT. However, the low upconversion efficiency poses a strong limit on further development of PDT. The core/shell structure Yb/Tm/GZO@SiO2 UCNPs are designed, which can form multistep cascade energy transfer from sillica shell to core Ga-doped Yb/Tm/ZnO. Compared with Yb/Tm/ZnO upconversion (UC) semiconductor nanoparticles (SNCs), the multistep cascade energy transfer process provides about seven times enhanced UCL emission. For the UCL-optimized core/shell upconversion SNCs of Yb-2/Tm-0.5/G(3)ZO@mSiO(2), the Yb3+ energy transfer efficiency is determined to be as high as similar to 81% under 980 nm laser excitation. In addition, the Yb-2/Tm-0.5/G(3)ZO@mSiO(2) core/shell UCNPs have an excellent PDT treatment for Hela cells under 980 nm laser excitation.