The fact that high-strength concrete is easily to crack has a significant negative impact on its durability and strength. This paper gives an optimum design method of high-strength concrete for improving crack resistance based on orthogonal test artificial neural networks (ANN) and genetic algorithm. First, orthogonal test is operated to determine the influence of the concrete mix proportion to the slump, compressive strength, tensile strength, and elastic modulus, followed by calculating and predicting the concrete performance using ANN. Based on results from orthogonal test and ANN, a functional relationship among slump, compressive strength, tensile strength, elastic modulus, and mix proportion has been built. On this basis, using the widely used shrinkage and creep models, the functional relationship between the concrete cracking risk coefficient and the mix proportion is derived, and finally genetic algorithm is used to optimize the concrete mix proportion to improve its crack resistance. The research results showed that, compared with the control concrete, the cracking risk coefficient of the optimized concrete was reduced by 25%, and its crack resistance was significantly improved.