Combining photoacoustic (PA) imaging with laser speckle (LS) imaging (LSI) can simultaneously determine total hemoglobin concentration (HbT), hemoglobin oxygen saturation (SO2), and blood flow rates. Thus, the co-registration of PA and LS images is important in physiological studies and pathological diagnosis. This letter presents a co-registration algorithm combining mutual information with the maximum between-class variance segmentation method (Otsu method). The mutual information and Otsu method are used to provide the registration measure criterion and image feature recognition, respectively. The evaluation results show that the registration function possesses a single maximum peak and high smoothness across the global co-registration district, indicating a robust behavior. Moreover, this method has good registration accuracy, and the fusion result simultaneously visualizes the separate functional information of two kinds of images.