<p>Cannabis use disorder is particularly prevalent and impairing among young people, and evidence-based treatments are limited. Prior trials of N-acetylcysteine, added to contingency management as a platform behavioral intervention, yielded positive findings in youth but not in adults. This trial sought to rigorously evaluate whether N-acetylcysteine is efficacious in youth when not paired with a robust behavioral treatment platform. Treatment-seeking youth with cannabis use disorder (<i>N</i> = 192, ages 14–21) were randomized to receive a double-blind 12-week course of oral N-acetylcysteine 1200 mg or placebo twice daily; all received weekly medical management and brief behavioral counseling. The primary efficacy outcome was the proportion of negative urine cannabinoid tests during treatment, compared between groups. An array of self-report and urine testing measures were examined secondarily to assess cannabis use reduction and cessation outcomes. The N-acetylcysteine and placebo groups did not differ in proportion of negative urine cannabinoid tests (RR = 0.93, 95% CI = 0.53, 1.64; <i>p</i> = 0.80) or self-reported cannabis abstinence (RR = 1.02, 95% CI = 0.63, 1.65; <i>p</i> = 0.93) during treatment. The mean percentage of cannabis use days and grams of cannabis used per using day decreased over time during treatment but did not differ between groups. More N-acetylcysteine than placebo treated participants reported gastrointestinal adverse events (63/98 versus 37/94, χ²₁ = 11.9 <i>p</i> &lt; 0.001); adverse events were otherwise similar between groups. Findings indicate that N-acetylcysteine is not efficacious for youth cannabis use disorder when not paired with contingency management, highlighting the potentially crucial role of a robust behavioral treatment platform in facilitating prior positive efficacy findings with N-acetylcysteine.</p><p>Trial Registration: Clinicaltrials.gov identifier NCT03055377</p>