Landslides have posed a huge threat to the ecological environment and human society all over the world. As the most conventional reinforcement method, anti-slide piles are widely used in the reinforcement of slopes. Currently, more and more attentions have been paid to the low-cost and high-efficiency optimal design of anti-slide piles. However, limitations in the method of the optimization design for slope reinforced with piles still exist. In this paper, a new multi-objective comprehensive optimization method was proposed for the optimization of the slope reinforced with anti-slide piles. The factor of safety, internal force and deflection of piles were selected as the optimization indexes and the optimization index weight was determined by integrating the subjective and objective weight. The influence of the pile location, pile length and pile spacing on the reinforcement effect was analyzed by the numerical simulation. Through the simulation case analysis, the proposed model had achieved good effects on the optimization design of anti-slide piles, which could effectively reduce the engineering costs. The optimization results showed that the best reinforcement effect for the homogeneous slope could be obtained when the anti-slide piles with the critical pile length and small pile spacing was located in the middle of the slope. This provides a new solution for the optimization design of other types of complex slopes, and has broad application prospects.