<p>This paper addresses the design of a guidance and control system for missile interception of high-maneuvering targets. A guidance-control-integrated model based on a strict feedback state equation is proposed, taking into account issues such as rudder delay and constraints on the missile–target LOS angle at the terminal guidance stage. To estimate both internal and external disturbances, a novel disturbance observer is employed. In order to overcome the difficulty of controller parameter adjustment, a specific cost function and constraint conditions are formulated, and the ISSA algorithm is applied to optimize the tuning of the PIDSMC controller parameters. Comparison with SSA-PIDSMC, PSO-PIDSMC, PIDSMC, GTSMC, and BPN algorithms through simulation results demonstrates that the ISSA-PIDSMC algorithm has a clear advantage in parameter optimization, effectively improving the convergence rate of the sliding mode surface and missile–target LOS angle. Moreover, it minimizes energy consumption under constraints, avoids chattering phenomena, and exhibits optimal stability and dynamic performance. Furthermore, the ISSA-PIDSMC algorithm shows excellent robustness and adaptability in environments with different initial positions and multiple disturbance sources, accurately estimating and compensating for disturbances. This significantly enhances the interference rejection capability and interception accuracy of the guidance control system, making it suitable for high-precision, high-dynamic response missile defense systems.</p>