SignificanceAs the prevalence of pediatric obesity continues to rise, determining neurobiological mechanisms underlying longitudinal childhood weight gain is critically important for informing early intervention and prevention strategies. We use an MRI technique to probe nucleus accumbens (NAcc) tissue microstructure and predict waist circumference after 1 y. We find that increased cell density in the NAcc is strongly associated with obesity in a large cohort of children and predicts future weight gain independent of waist circumference at baseline. These results extend animal studies showing a vicious cycle in which diet-induced neuroinflammation leads to disruption of the brain’s reward circuitry and subsequently promotes further unhealthy eating and weight gain.