Abstract Background Metabolic and bariatric surgery improves most obesity-related comorbidities. Here, we evaluate the effect of different metabolic and bariatric surgery interventions on the use of medications to treat chronic conditions. Materials and Methods This was an observational population-based cohort study performed in Lombardy, Italy. Healthcare utilization databases were used to identify all residents who underwent a metabolic and bariatric surgery procedure between 2010 and 2020 with available follow-up data for at least three years after surgery. We included patients undergoing laparoscopic sleeve gastrectomy (LSG), gastric bypass (GB), laparoscopic adjustable gastric banding (LAGB), and biliopancreatic diversion (BPD). Results During the period 2010 to 2020, 19,450 patients (22.5% males, 13.5% with diabetes) underwent a metabolic and bariatric surgery procedure. LSG was the most commonly performed procedure (65%), followed by LAGB (19%), GB (15%), and BPD (1%). There was a significant reduction in the use of glucose-lowering and antihypertensive drugs after the procedure in all groups. Compared to LSG, the reduction in the use of glucose-lowering drugs was greater following GB (reduction at 3 years: 59 vs 65%, p-interaction < 0.001) and lower following LAGB (59 vs 25%, p-interaction < 0.001). There was a significant reduction in lipid-lowering drug use following LSG and GB (3-year reduction: 21 and 50%, p-interaction < 0.001), and in psychiatric drug use following LSG, GB, and LAGB (with no difference between groups). In all groups, proton pump inhibitor use increased during the first 6 months, followed by a decrease from 1 year afterward. Conclusion The present study including a large number of patients undergoing metabolic and bariatric surgery procedures shows robust reductions in the use of glucose, blood pressure and lipid-lowering drugs at 3 years follow-up, suggesting benefits of surgery on both quality of life and healthcare costs.