The most common type of liver cancer is hepatocellular carcinoma (HCC), which begins in hepatocytes. The HCC, like most types of cancer, does not show symptoms in the early stages and hence it is difficult to detect at this stage. The symptoms begin to appear in the advanced stages of the disease due to the unlimited growth of cancer cells. So, early detection can help to get timely treatment and reduce the mortality rate. In this paper, we proposes a novel machine learning model using seven classifiers such as K-nearest neighbor (KNN), random forest, Naïve Bayes, and other four classifiers combined to form stacking learning (ensemble) method with genetic optimization helping to select the features for each classifier to obtain highest HCC detection accuracy. In addition to preparing the data and make it suitable for further processing, we performed the normalization techniques. We have used KNN algorithm to fill in the missing values. We trained and evaluated our developed algorithm using 165 HCC patients collected from Coimbra’s Hospital and University Centre (CHUC) using stratified cross-validation techniques. There are total of 49 clinically significant features in this dataset, which are divided into two groups such as quantitative and qualitative groups. Our proposed algorithm has achieved the highest accuracy and F1-score of 0.9030 and 0.8857, respectively. The developed model is ready to be tested with huge database and can be employed in cancer screening laboratories to aid the clinicians to make an accurate diagnosis.