Purpose <p>To evaluate the impact of cannabis use, tobacco smoking, and their concurrent use on postoperative complications following open carpal tunnel release (CTR) using a nationwide database.</p> Methods <p>A retrospective cohort study was conducted using the PearlDiver database (2010–2022) to identify adult patients who underwent open CTR. Patients were categorized into four groups: cannabis-only users (<i>n</i> = 800), tobacco-only users (<i>n</i> = 167,803), concurrent users (<i>n</i> = 3529), and non-users (<i>n</i> = 167,803 matched controls). Postoperative complications, surgical site infection, wound disruption, joint stiffness, and complex regional pain syndrome, were assessed at 6 weeks and 3 months postoperatively.</p> Results <p>At 6 weeks and 3 months, surgical site infection was more common among concurrent cannabis and tobacco users, cannabis-only users, and tobacco-only users. Wound disruption occurred more frequently in concurrent users and tobacco-only users, but not in cannabis-only users. Complex regional pain syndrome was associated only with tobacco use. No association was found between any substance use and joint stiffness.</p> Conclusion <p>Cannabis use, tobacco smoking, and especially concurrent use increase the risk of surgical site infection and wound disruption following open CTR. Tobacco use is independently associated with complex regional pain syndrome, while cannabis may have a protective effect. These findings emphasize the need for preoperative screening and patient education.</p> Type of study/level of evidence <p>Retrospective cohort study/level III.</p>