In order to improve the scientificity of the comprehensive transportation hub layout and promote the construction of regional economy and the benign development of the transportation industry, an optimization method of the comprehensive transportation hub layout was studied and designed based on the immune neural network algorithm. The key factors of the comprehensive transportation hub layout optimization was extracted,constraints were set, BP neural network algorithm was applied, the comprehensive transportation hub layout optimization model was established, and immune clone algorithm was introduced to obtain the optimal solution results of the comprehensive transportation hub layout optimization model. The test results show that the average execution time of the optimization results obtained by this method is 0.56s for 10 random groups of historical data of comprehensive transportation hub planning, which is real-time and efficient. The mean value of the absolute value of the error of the layout optimization results is 0.043, and the absolute value of the maximum error is 0.074, both of which are controlled within the range of ±0.1 required by the actual project, which is accurate and feasible.