Recently, many diseases have negatively impacted people’s lifestyles. Among these, knee osteoarthritis (OA) has been regarded as the primary cause of activity restriction and impairment, particularly in older people. Therefore, quick, accurate, and low-cost computer-based tools for the early prediction of knee OA patients are urgently needed. In this paper, as part of addressing this issue, we developed a new method to efficiently diagnose and classify knee osteoarthritis severity based on the X-ray images to classify knee OA in (i.e., binary and multiclass) in order to study the impact of different class-based, which has not yet been addressed in previous studies. This will provide physicians with a variety of deployment options in the future. Our proposed models are basically divided into two frameworks based on applying pre-trained convolutional neural networks (CNN) for feature extraction as well as fine-tuning the pre-trained CNN using the transfer learning (TL) method. In addition, a traditional machine learning (ML) classifier is used to exploit the enriched feature space to achieve better knee OA classification performance. In the first one, we developed five classes-based models using a proposed pre-trained CNN for feature extraction, principal component analysis (PCA) for dimensionality reduction, and support vector machine (SVM) for classification. While in the second framework, a few changes were made to the steps in the first framework, the concept of TL was used to fine-tune the proposed pre-trained CNN from the first framework to fit the two classes, three classes, and four classes-based models. The proposed models are evaluated on X-ray data, and their performance is compared with the existing state-of-the-art models. It is observed through conducted experimental analysis to demonstrate the efficacy of the proposed approach in improving the classification accuracy in both multiclass and binary class-based in the OA case study. Nonetheless, the empirical results revealed that the fewer multiclass labels used, the better performance achieved, with the binary class labels outperforming all, which reached a 90.8% accuracy rate. Furthermore, the proposed models demonstrated their contribution to early classification in the first stage of the disease to help reduce its progression and improve people’s quality of life.