It is crucial to optimize the size of Au@semiconductor core-shell nanospheres for the application of nanoparticles in biological imaging. In this study, the influence of the core radius and shell thickness of Au@ semiconductor core-shell nanospheres on their backscattering spectra is quantitively analyzed using Mie scattering theory and a refractive index size correction model for metal nanoparticles. The results indicate that by changing the size parameters, the resonance wavelength of Au@semiconductor nanospheres can be tuned to within the first near-infrared biological window. Moreover, the size of Au@semiconductor nanospheres is optimized at three commonly used laser wavelengths (800 nm, 830 nm, and 900 nm). The results show that the optimal core radius and shell thickness are 60?80 nm and 18?20 nm, respectively. Au@TiO₂ nanospheres exhibit good backscattering ability among the three types of nanoparticles. Given the presence of certain errors in the material preparation process, a size range is also determined when the volume backscattering coefficient is greater than 95% of its maximum value. Finally, the influence of biological tissue refractive index and incident laser wavelength on the optimization results is analyzed. Research has shown that an increase in the refractive index of biological tissues leads to an enhancement of backscattering ability, whereas an increase in the wavelength of the incident laser weakens backscattering ability. Hence, optimized Au@semiconductor nanospheres can serve as ideal contrast agents in biological imaging.