An abnormality that develops in white blood cells is called leukemia. The diagnosis of leukemia is made possible by microscopic investigation of the smear in the periphery. Prior training is necessary to complete the morphological examination of the blood smear for leukemia diagnosis. This paper proposes a Histogram Threshold Segmentation Classifier (HTsC) for a decision support system. The proposed HTsC is evaluated based on the color and brightness variation in the dataset of blood smear images. Arithmetic operations are used to crop the nucleus based on automated approximation. White Blood Cell (WBC) segmentation is calculated using the active contour model to determine the contrast between image regions using the color transfer approach. Through entropy-adaptive mask generation, WBCs accurately detect the circularity region for identification of the nucleus. The proposed HTsC addressed the cytoplasm region based on variations in size and shape concerning addition and rotation operations. Variation in WBC imaging characteristics depends on the cytoplasmic and nuclear regions. The computation of the variation between image features in the cytoplasm and nuclei regions of the WBCs is used to classify blood smear images. The classification of the blood smear is performed with conventional machine-learning techniques integrated with the features of the deep-learning regression classifier. The designed HTsC classifier comprises the binary classifier with the classification of the lymphocytes, monocytes, neutrophils, eosinophils, and abnormalities in the WBCs. The proposed HTsC identifies the abnormal activity in the WBC, considering the color and shape features. It exhibits a higher classification accuracy value of 99.6% when combined with the other classifiers. The comparative analysis expressed that the proposed HTsC model exhibits an overall accuracy value of 98%, which is approximately 3%–12% higher than the conventional technique.