Mean-based thresholding methods are among the most popular techniques that are used for images segmentation. Thresholding is a fundamental process for many applications since it provides a good degree of intensity separation of given images. Minimum cross-entropy thresholding (MCET) is one of the widely used mean-based methods for images segmentation; it is based on a classical mean that remains steady and limited value. In this paper, to improve the efficiency of MCET, dedicated mean estimation approaches are proposed to be used with MCET, instead of using the classical mean. The proposed mean estimation approaches, for example, alpha trim, harmonic, contraharmonic, and geometric, tend to exclude the negative impact of the undesired parts from the mean computation process, such as noises, local outliers, and gray intensity levels, and then provide an improvement for the thresholding process that can reflect good segmentation results. The proposed technique adds a profound impact on accurate images segmentation. It can be extended to other applications in object detection. Three data sets of medical images were applied for segmentation in this paper, including magnetic resonance imaging (MRI) Alzheimer’s, MRI brain tumor, and skin lesion. The unsupervised and supervised evaluations were used to conduct the efficiency of the proposed method.