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Image registration is the process of overlaying images of the same scene taken at different times by different sensors from different viewpoints. The cross‐cumulative residual entropy (CCRE)‐based medical image registration could achieve a high precision and a strong robustness performance. However, the optimization problem formulated by CCRE consists of some local extrema, especially for noise images. In order to address these difficulties, this article proposes a new optimization algorithm named hybrid differential search algorithm (HDSA) to optimize CCRE. As HDSA consists of simple control parameters, it is independent of the initial searching point. In addition, HDSA ameliorated the search method and the iterative conditions. As a result, the optimization process is more stable and efficient. Image registration experiments of HDSA are performed and compared with the conventional differential search algorithm (DSA) and adaptive differential evolution with optional external archive (JADE). The results show that HDSA does not only overcome the difficulties of sticking in the local extrema but also enhances the precision of registration. It is effective, robust, and fast for both the single‐mode rigid medical image registration and the multispectral‐mode rigid medical image registration.