Diabetic macular edema (DME) is the most common cause of visual impairment among patients with diabetes mellitus. Anti-vascular endothelial growth factors (Anti-VEGFs) are considered the first line in its management. The aim of this research has been to develop a deep learning (DL) model for predicting response to intravitreal anti-VEGF injections among DME patients. The research included treatment naive DME patients who were treated with anti-VEGF. Patient’s pre-treatment and post-treatment clinical and macular optical coherence tomography (OCT) were assessed by retina specialists, who annotated pre-treatment images for five prognostic features. Patients were also classified based on their response to treatment in their post-treatment OCT into either good responder, defined as a reduction of thickness by >25% or 50 µm by 3 months, or poor responder. A novel modified U-net DL model for image segmentation, and another DL EfficientNet-B3 model for response classification were developed and implemented for predicting response to anti-VEGF injections among patients with DME. Finally, the classification DL model was compared with different levels of ophthalmology residents and specialists regarding response classification accuracy. The segmentation deep learning model resulted in segmentation accuracy of 95.9%, with a specificity of 98.9%, and a sensitivity of 87.9%. The classification accuracy of classifying patients’ images into good and poor responders reached 75%. Upon comparing the model’s performance with practicing ophthalmology residents, ophthalmologists and retina specialists, the model’s accuracy is comparable to ophthalmologist’s accuracy. The developed DL models can segment and predict response to anti-VEGF treatment among DME patients with comparable accuracy to general ophthalmologists. Further training on a larger dataset is nonetheless needed to yield more accurate response predictions.