The application of a cryogenic liquefied natural gas expander can reduce the production of flash steam and improve the efficiency of natural gas liquefaction. Like traditional hydraulic machinery, cavitation will occur during the operation of a liquefied natural gas expander, in particular, there is a strong vortex flow in the draft tube, and the cavitation phenomenon is serious. In this paper, the energy loss coefficient of the draft tube is used to describe the cavitation flow in the draft tube, and the goal of reducing the cavitation in the draft tube is achieved through the optimization design of the runner. Different runner models within the range of design parameters were obtained using the Latin hypercube test, and the relationship between design parameters and objective functions is constructed by a second-order response surface model. Finally, the optimized runners were obtained using a genetic algorithm. The effects of blade loading distribution and blade lean angles on the cavitation in the draft tube were studied. According to the optimization results, the blade loading distribution and blade lean angles are recommended in the end.