Background: Diabetic macular edema (DME) is a leading cause of vision impairment in diabetes, driven by vascular endothelial growth factor (VEGF)-mediated vascular permeability. Anti-VEGF therapies have revolutionized DME management, but their long-term efficacy and treatment burden require evaluation. Objective: To assess the long-term efficacy, durability, treatment burden, and safety of anti-VEGF therapy in patients with DME. Methods: A retrospective observational study included 195 DME patients treated with anti-VEGF agents. Baseline and follow-up data (12, 36, and 60 months) on best-corrected visual acuity (BCVA), central retinal thickness (CRT), and treatment adherence were analyzed. Statistical methods included paired t-tests and Kaplan-Meier survival analysis. Results: Patients demonstrated a mean BCVA improvement of +13 letters at 12 months, with stabilization at +7 letters by 60 months. CRT decreased by 155 µm in the first year and remained stable over five years. While 58% of patients sustained therapeutic gains at five years, adherence to follow-ups declined from 85% to 70%. The average injection frequency decreased from 6/year in year one to 4/year in subsequent years. Adverse events included intraocular pressure elevation (10%), endophthalmitis (1%), and mild cardiovascular complications (3%). Conclusion: Anti-VEGF therapy provides significant long-term benefits in managing DME, though declining efficacy and adherence over time highlight the need for personalized and innovative treatment strategies to sustain outcomes and reduce burden. Future research should focus on optimizing delivery methods and exploring adjunctive therapies.