BACKGROUND: Value-based care is an opportunity for medication optimization services to improve medication management and reduce health care spending. The reach of these services may be extended through telehealth. However, as health care systems and payers grapple with the long-term financing of telehealth, real-world assessments are needed to evaluate the potential economic impact of pharmacy-driven telehealth services. OBJECTIVE: To evaluate the impact of a scalable pharmacist-driven telehealth intervention to improve medication management on health care spending for clinically complex patients who were enrolled in a Medicare Next Generation Accountable Care Organization. METHODS: Data for this pretest-posttest nonequivalent group design study came from Medicare claims from 2015 to 2020 and linked pharmacist care activity data derived from the electronic medical record. Patients in the intervention group were identified as those who received the telehealth medication management service. Patients in the control group were offered the service and refused or could not be contacted. The primary outcome was total medical spending over a 6-month period, and impact was assessed using a covariate-adjusted difference-in-difference model. RESULTS: There were 581 patients who received the intervention and 1,765 who served as controls. The telehealth intervention reduced total medical spending by $2,331.85 per patient over the first 6 months of the service ($388.50 per month; P = 0.0261). Across a range of estimates for the cost of service delivery, we find a return on investment of 3.6:1 to 5.2:1. CONCLUSIONS: The $388.50 monthly savings found in this study represent a substantial reduction in health care spending and emphasize the opportunity for telehealth delivery of medication management services to improve value as a part of alternative payment models. DISCLOSURES: This study was funded by the UNC Health Care Department of Pharmacy. Dr Urick has received personal fees from Pharmacy Quality Solutions and Cardinal Health. Drs Peters, Vest, Colmenares, Foushee, and DeFalco are employees of UNC Health Care Department of Pharmacy. Mr Easter received a Co-PI grant from NACDS Foundation to implement Community-based Value Care Initiative (CVCI) in a community pharmacy setting. He also received a grant to Eshelman School of Pharmacy. He has an individual consulting agreement with digital health company Truentity Health to provide go to market strategy for medication management services. He also has stock options from Truentity Health as a component of the consulting agreement. Dr Foushee has a leadership or fiduciary role at Member-At-Large and the Ambulatory Care Academy of the North Carolina Association of Pharmacists. At the time this work was conducted, Dr Urick, Dr Pathak, and Dr Blanchard were all employees of the UNC Eshelman School of Pharmacy.