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Objective: To examine the association of body mass index (BMI) with pain in people with hand osteoarthritis (OA), and explore whether this association, if causal, is mediated by systemic inflammatory biomarkers. Methods: In 281 Nor‐Hand study participants, we estimated associations between BMI and hand pain, as measured by the Australian/Canadian Osteoarthritis Hand Index (AUSCAN; range 0–20) and Numerical Rating Scale (NRS; range 0–10); foot pain, as measured by NRS (range 0–10); knee/hip pain, as measured by the Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC; range 0–20); painful total body joint count; and pain sensitization. We fit natural‐effects models to estimate natural direct and natural indirect effects of BMI on pain through inflammatory biomarkers. Results: Each 5‐unit increase in BMI was associated with more severe hand pain (on average increased AUSCAN by 0.64 [95% confidence interval (95% CI) 0.23, 1.08]), foot pain (on average increased NRS by 0.65 [95% CI 0.36, 0.92]), knee/hip pain (on average increased WOMAC by 1.31 [95% CI 0.87, 1.73]), generalized pain, and pain sensitization. Mediation analyses suggested that the effects of BMI on hand pain and painful total body joint count were partially mediated by leptin and high‐sensitivity C‐reactive protein (hsCRP), respectively. Effect sizes for mediation by leptin were larger for the hands than for the lower extremities, and were statistically significant for the hands only. Conclusion: In people with hand OA, higher BMI is associated with greater pain severity in the hands, feet, and knees/hips. Systemic effects of obesity, measured by leptin, may play a larger mediating role for pain in the hands than in the lower extremities. Low‐grade inflammation, measured by hsCRP, may contribute to generalized pain in overweight/obese individuals. [ABSTRACT FROM AUTHOR]