Phellinus linteus, a medicinal mushroom with potent antioxidant properties, contains bioactive compounds, such as polyphenols and flavonoids. To optimize the extraction of skin-whitening compounds, ultrasound-assisted extraction combined with statistically based optimization was used to simultaneously extract total polyphenol content (TPC), radical scavenging activity (RSA), and tyrosinase activity inhibition (TAI). Extraction variables, including extraction time (X1:4.8 ~ 55.2 min), extraction temperature (X2:26.4 ~ 93.6oC), and ethanol concentration (X3:13.0 ~ 97.0%), were varied in 17 experimental cycles based on a central composite design. Quadratic regression models for TPC, RSA, and TAI had coefficients of determination (R2) greater than 0.92, demonstrating well-fitted models and statistical significance. Analysis of variance revealed that all three variables significantly influenced extraction efficiency (p < 0.0041), with ethanol concentration (X3) having the most pronounced effect. The optimal extraction conditions were 80.0 min, 82.5oC, and 64.8% ethanol, yielding predicted values of 6.42 mg GAE/g DM for TPC, 73.71% for RSA, and 85.04% for TAI. These results suggest that a moderate ethanol concentration combined with adequate thermal input maximizes the extraction of antioxidant and tyrosinase inhibitory activities specifically associated with skin-whitening effects.