Abstract Background and aims Although cannabis use is widespread and prevalence of cannabis use disorder (CUD) is increasing, limited advancements have been made in CUD medication development. The objective of this study was to test the efficacy of varenicline with medical management for reducing cannabis use in treatment‐seeking individuals with CUD. Design A phase 2, randomized, double‐blind, parallel group, placebo‐controlled trial was conducted. Setting Two outpatient research clinics in South Carolina, USA, from February 2020 to February 2023. Participants Eligible participants met Diagnostic and Statistical Manual of Mental Disorders , Fifth Edition (DSM‐5) criteria for CUD and used cannabis a minimum of 3 days per week. One hundred and seventy‐four participants were randomized to either varenicline ( n = 90) or placebo ( n = 84) stratified by smoking status and sex. Interventions Varenicline (titrated to goal dose of 1 mg twice daily) or matching placebo for 12 weeks. Medical management was provided weekly. Measurements Primary outcome measure was reduction in total number of cannabis use sessions at each weekly visit (weeks 6–12). Findings There was no main effect of treatment on reduction of total number of cannabis use sessions per week during weeks 6 through 12 [between group difference (Δ) = 1.7; 95% confidence interval (CI) = −1.0 to 4.7; P = 0.41]; however, a statistically significant treatment by sex interaction was found (F 1,132 = 5.1; P = 0.026), with a statistically significant effect of varenicline on reduction of cannabis use sessions per week observed in men (Δ = 4.2; 95% CI = 0.6–7.8; P = 0.04) but not women (Δ = −1.4; 95% CI = −5.7 to 3.0; P = 0.18). Conclusions Varenicline with medical management resulted in decreased cannabis use among men with cannabis use disorder seeking treatment, but not women (no effect was observed on the overall sample of treatment‐seeking individuals with cannabis use disorder).