The red upconversion (UC) emission of Ho³⁺ ions is located in an “optical window” range of the biological tissue, which has great prospects in the biology application. In this work, the NaYF₄:20%Yb³⁺/2%Ho³⁺/12%Ce³⁺@NaYF₄:x%Yb³⁺ and NaYF₄:20%Yb³⁺/2%Ho³⁺/12%Ce³⁺@NaYF₄:15%Yb³⁺/x%Nd³⁺ core-shell (CS) nanoparticles (NPs) are built based on the epitaxial growth technology by the high-temperature co-precipitation method in order to enhance red UC emission. The crystal structure and morphology of NaYF₄ CS NPs are characterized by X-ray diffraction and transmission electron microscope. It can be found that the morphology of NaYF₄ CS NPs changes from sphere into rod shape when coated with NaYF₄ shell, and has a pure hexagonal-phase crystal structure. Under 980 nm excitation, the red UC emission intensity of NaYF₄:20%Yb³⁺/2%Ho³⁺/12%Ce³⁺@NaYF₄:5%Yb³⁺ CS NPs is strongest and enhanced about 5.2 times than that of NaYF₄:20%Yb³⁺/2%Ho³⁺/12%Ce³⁺ NPs. Under 800 nm excitation, the red emission intensity of NaYF₄:20%Yb³⁺/2%Ho³⁺/12%Ce³⁺@NaYF₄:15%Yb³⁺/20%Nd³⁺ CS NPs is increased about 6.1 times compared with that of the NaYF₄:20%Yb³⁺/2%Ho³⁺/12%Ce³⁺@NaYF₄:15%Yb³⁺/5%Nd³⁺ CS NPs. This is because the constructed CS effectively reduces the non-radiative decay from the surface defects of NPs, and the doped Yb³⁺ and Nd³⁺ ions in the NaYF₄ shells can transfer more excitation energy to Ho³⁺ ions in the core. In addition, the NaYF₄: 20%Yb³⁺/2%Ho³⁺/12%Ce³⁺@NaYF₄:15%Yb³⁺/20%Nd³⁺ CS NP is excited by dual-wavelengths co-excitation (800 nm + 980 nm). It is found that the red UC emission intensity under the co-excitation of dual-wavelengths is higher than the sum of the excitation intensities of two single wavelengths (800 nm and 980 nm), which is due to the synergistic effect generated under the co-excitation of 980 nm and 800 nm near infrared laser. Therefore, different CS structures constructed by introducing different energy transfer channels can achieve the enhancement of the red UC emission under different excitation conditions, and the dual-wavelength co-excitation provides a new way to improve the penetration depth and the detection sensitivity for further expanding the applications in the field of biomedicine.