Internal cooling galleries are widely employed to mitigate piston thermal loads in gasoline engines, where their configuration plays a critical role in temperature distribution and component durability. In this study, Cradle CFD was coupled with the Conjugate Heat Transfer (CHT) and Volume of Fluid (VOF) multiphase approaches to investigate the effects of inlet angle and guide vane geometry on piston thermal performance. The SST k-ω turbulence model was adopted to resolve the transient flow behavior associated with reciprocating motion, while the Box-Behnken design methodology was applied to develop empirical correlations for optimization. The results demonstrate that an inlet angle of 10° delivers the most effective thermal performance, reducing the maximum and minimum piston temperatures by 1.69°C and 28.34°C, respectively, while also producing the highest heat transfer coefficient. In contrast, a 15° inlet angle promotes excessive turbulence and flow instability, leading to diminished cooling effectiveness. For the inlet geometry, the configuration defined by L₁ = 1.15 mm and L₂ = 16.3 mm achieves the highest area-averaged heat transfer coefficient of 1755.13 W/(m²·K) at 270°CA. Subsequent response surface optimization identifies L₁ = 2.3 mm and L₂ = 14.0 mm as the optimal design parameters, corresponding to a time-averaged heat transfer coefficient of 1928.513 W/(m²·K).