The multi-laminated controlled release system has been widely used in the modern pharmaceutical industry because of its simple structure and safety, which can control the drug release behavior by regulating its internal parameters. To achieve three desired drug release behaviors of constant rate, linear reduction, and nonlinearity, which can be controlled by the optimization of the controllable parameters in the controlled release system, such as initial concentration and diffusion coefficient, a new regularization cuckoo search algorithm based on the cuckoo search algorithm and Tikhonov regularization method is proposed. The numerical examples confirm the stability, effectiveness, and feasibility of the proposed method. The effect of the number of model layers on the optimization results is also analyzed.