Background: Opioid misuse is a public health crisis. Initial opioid exposures often occur post-operatively, and 10% of opioid-naïve patients who undergo cancer surgery subsequently become long-term opioid users. It has been shown that 70% of opioids prescribed post-operatively go unused, but only 9% of unused pills are disposed of appropriately, which increases the risk of unintended use. We evaluated the impact of an inexpensive, password-protected pill-dispensing device with mail return capacity on disposal of unused pills after cancer surgery. Methods: We conducted a prospective, proof-of-concept pilot study among adult patients scheduled for major cancer-related surgery. Enrolled patients received opioid prescriptions in a pill-dispensing device (Addinex) from a specialty pharmacy. The mechanical device linked to a smartphone app, which provided passwords on a prescriber-defined schedule. Patients were able to enter unique passwords into the device to receive their pills if the prescribed time had elapsed. The smartphone app provided clinical guidance based on patient-reported pain levels, and suggested tapering strategies. Patients were instructed to return the device in a DEA-approved mailer when opioid use was no longer required for acute pain control. Unused pills were destroyed upon receipt. The primary objective was to determine the feasibility of device return, defined as > 50% within 6 weeks. We also explored total pill use and return, patterns of device use and patient satisfaction. Results: We enrolled 30 patients between October 2020 and December 2021. The median age was 46 (range 29–72). Surgical procedures included abdominal hysterectomy (13), mastectomy and reconstruction (10), and soft tissue tumor resections (7). Overall, the majority of participants (n = 24, 80%) returned the device, and more than half (n = 17, 57%) returned the device within 6 weeks of surgery. There were 19 patients who obtained opioids from the device. Among these patients, the majority were satisfied with the device (n = 14, 74%); felt the benefits of the device justified the added steps involved (n = 14, 74%); and would sign up to receive opioids in the device again (n = 13, 68%). The other 11 patients used no opioids. None of these non-users reported any opioid requirements for pain control, and all but one (n = 10, 91%) returned the device and unused pills. In total, 567 opioids were prescribed, and 170 (30%) were used. Of the 397 excess pills, 332 (84% of unused pills, 59% of all pills prescribed) were returned by mail. Conclusions: We found that use of an inexpensive pill-dispensing device with mail return capacity was a feasible and effective strategy to enhance disposal of unused post-operative opioids. Interestingly, a substantial number of prescribed pills were unused. This system also improves confidence with indicated opioid use while reducing diversion.