Under the condition of unit degradation, the comprehensive optimization research on the large-scale system reliability design and the preventive maintenance strategy considering the life-cycle becomes more complicated. For the case that unit failure obeys Weibull distribution, considering the multi-unit preventive joint maintenance model, the life-cycle cost optimization model of large-scale system under reliability constraint is constructed. The problem of exponential growth of combination size caused by the large number of units leads to the difficulty of nonlinear optimization. Genetic algorithm programming is used to solve the global optimal solution, including the unit reliability in the design stage and the system preventive maintenance period in the operation stage. Finally, through the analysis of typical examples, the correctness and effectiveness of the model and algorithm are verified, and the relationship among decision variables such as the maintenance improvement factor, the unit reliability and the preventive maintenance cycle is explored. The research results are helpful to simplify the process of reliability and maintainability integrated design optimization for system engineers and have certain theoretical and application value.