This study aimed to optimize the ultrasound-assisted extraction process of Hippophae rhamnoides leaf polyphenols (HRLP) and evaluate their antioxidant and lipid-lowering activities. The effects of four factors—ultrasonic time, solid-to-liquid ratio, ultrasonic power, and temperature—on HRLP yield were investigated. Based on single-factor experiments, the extraction parameters were optimized using the Box-Behnken response surface methodology. The HRLP obtained under optimal conditions was further subjected to in vitro experiments to validate its antioxidant and lipid-lowering activities. Results showed that the maximum polyphenol yield of 18.07 ± 0.74 mg/g was achieved under the optimal conditions: ultrasonic time of 42 min, temperature of 61 °C, power of 410 W, and solid-to-liquid ratio of 1∶47 (g/mL). The HRLP exhibited IC₅₀ values of 0.11, 0.25, and 0.54 mg/mL for scavenging ABTS, DPPH, and hydroxyl radicals, respectively, and its ferric ion reducing capacity was approximately 1/6 that of vitamin C. In lipid-lowering studies, HRLP demonstrated a maximum oil-binding capacity of 38.7 mg/g, a bile acid binding rate of 62.45%, and pancreatic lipase inhibitory activity with an IC₅₀ of 0.85 mg/mL. The extraction process proved stable and feasible, yielding HRLP with significant antioxidant and lipid-lowering properties. The novel method established in this study features simple operation and enables efficient preparation of HRLP, providing innovative strategies for its industrial-scale production.