This study compared the effectiveness of genetic algorithm-back propagation neural network (GA-BPNN) and response surface methodology (RSM) in optimizing the high-pressure ultrasound-assisted enzymatic extraction of collagen from sheep skin to determine the optimal process parameters. The results showed that GA-BPNN had superior performance in model fitting and prediction compared to RSM. The optimal extraction parameters were as follows: high pressure holding time of 23 min, ultrasound time of 22 min, enzyme dosage of 3.2%, and hydrolysis time of 222 min. Under these conditions, the extraction rate of collagen from sheep skin was (80.5 ± 1.6)%, which is 40% higher than that of the traditional papain method. The results of ultraviolet-visible (UV-Vis) spectroscopy and Fourier transform infrared (FTIR) spectroscopy demonstrated that the structure of the extract collagen was complete.