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Many patients with fibromyalgia (FM) report using cannabis as a strategy to improve pain. Given that pain often co‐occurs with symptoms of anxiety and depression (i.e., negative affect) and sleep problems among patients with FM, improvements in these symptoms might indirectly contribute to reductions in pain intensity following cannabis use. The main objective of the study was to examine whether changes in pain intensity following initiation of medical cannabis among patients with FM could be attributed to concurrent changes (i.e., reductions) in negative affect and sleep problems. This was a 12‐month prospective cohort study among patients with FM (n = 323) initiating medical cannabis under the care of physicians. Patients were assessed at baseline, and follow‐up assessment visits occurred every 3 months after initiation of medical cannabis. Patients’ levels of pain intensity, negative affect, and sleep problems were assessed across all visits. Multilevel mediation analyses indicated that reductions in patients’ levels of pain intensity were partly explained by concurrent reductions in sleep problems and negative affect (both P< 0.001). This remained significant even when accounting for patients’ baseline characteristics or changes in medical cannabis directives over time (all P> 0.05). Our findings provide preliminary insight into the potential mechanisms of action underlying pain reductions among patients with FM who are using medical cannabis. Given the high attrition rate (i.e., 75%) observed in the present study at 12 months, our findings cannot be generalized to all patients with FM who are using medical cannabis.