The least risk bomb location (LRBL) structure, as an explosion-proof structure applied to airliner, should reduce the structure quality as much as possible while ensuring reliability. This article conducts research on reliability based LRBL structural optimization design. Firstly, the lightweight LRBL structure was taken as the optimization design objective, and the structural size of the LRBL structure was selected as the design variable. Then, the structural reliability index was used as a constraint, and the response surface method combined with reliability index transformation was used to obtain the optimization model constraint function. The reliability optimization model of the LRBL structure was established. Finally, the interior point method was used to optimize the reliability of the LRBL structure. An optimization design case analysis was conducted using a certain LRBL structural design scheme, and the results show that on the basis of meeting reliability indicators, the optimized LRBL structural mass was reduced by 45.08%, with a significant weight reduction effect. This has guiding significance and reference value for the application of LRBL structures in engineering practice.