The gastrointestinal system contains the upper and lower gastrointestinal tracts. The main tasks of the gastrointestinal system are to break down food and convert it into essential elements that the body can benefit from and expel waste in the form of feces. If any organ is affected, it does not work well, which affects the body. Many gastrointestinal diseases, such as infections, ulcers, and benign and malignant tumors, threaten human life. Endoscopy techniques are the gold standard for detecting infected parts within the organs of the gastrointestinal tract. Endoscopy techniques produce videos that are converted into thousands of frames that show the disease’s characteristics in only some frames. Therefore, this represents a challenge for doctors because it is a tedious task that requires time, effort, and experience. Computer-assisted automated diagnostic techniques help achieve effective diagnosis to help doctors identify the disease and give the patient the appropriate treatment. In this study, many efficient methodologies for analyzing endoscopy images for diagnosing gastrointestinal diseases were developed for the Kvasir dataset. The Kvasir dataset was classified by three pre-trained models: GoogLeNet, MobileNet, and DenseNet121. The images were optimized, and the gradient vector flow (GVF) algorithm was applied to segment the regions of interest (ROIs), isolating them from healthy regions and saving the endoscopy images as Kvasir-ROI. The Kvasir-ROI dataset was classified by the three pre-trained GoogLeNet, MobileNet, and DenseNet121 models. Hybrid methodologies (CNN–FFNN and CNN–XGBoost) were developed based on the GVF algorithm and achieved promising results for diagnosing disease based on endoscopy images of gastroenterology. The last methodology is based on fused CNN models and their classification by FFNN and XGBoost networks. The hybrid methodology based on the fused CNN features, called GoogLeNet–MobileNet–DenseNet121–XGBoost, achieved an AUC of 97.54%, accuracy of 97.25%, sensitivity of 96.86%, precision of 97.25%, and specificity of 99.48%.