We perform a two-step segmentation of the hippocam-pus in histological images. First, we maximize the overlap of an empirically-derived parametric Deformable Model with two crucial landmark sub-structures in the brain image using Differential Evolution. Then, the points located in the previous step determine the region where a thresh-olding technique based on Otsu's method is to be applied. Finally, the segmentation is expanded employing Random Forest in the regions not covered by the model. Our approach showed an average segmentation accuracy of the 92.25% and 92.11% on test sets comprising 15 real and 15 synthetic images, respectively.