An optimal design method and system for slope reinforcement with anti-slide piles includes: modeling a slope type to obtain a three-dimensional (3D) slope numerical calculation model; establishing different numerical calculation models for anti-slide piles according to different reinforcement schemes of the anti-slide piles; determining optimization indexes through a coupling analysis of the 3D slope numerical calculation model and the anti-slide pile numerical calculation model; calculating a comprehensive optimization value according to the optimization index; determining an optimal anti-slide pile reinforcement scheme according to the comprehensive optimization value, and determining whether the optimal anti-slide pile reinforcement scheme meets the optimization objective; and carrying out slope reinforcement according to the optimal anti-slide pile reinforcement scheme if yes. A multi-objective comprehensive optimization model including an optimization index system and comprehensive weights of optimization indexes is established.