Background <p>Childhood obesity is associated with musculoskeletal symptoms. The interplay between adiposity, systemic inflammation, and musculoskeletal pain (MSP) remains not fully understood. This study aimed to investigate the associations of anthropometric measures, physical activity, and serum C-reactive protein (CRP) levels with MSP in children with excess weight.</p> Methods <p>In this cross-sectional study, 100 children with excess weight (52% male; mean age 11 ± 2.3 years) were recruited from a referral center in Isfahan. Physical examination and musculoskeletal abnormalities were assessed by a physiatrist. Anthropometric indices were measured using a calibrated body composition analyzer. Physical activity, Screen time, and MSP were assessed using the Physical Activity Questionnaire for Older Children (PAQ-C), the Screen Time Questionnaire (STQ), and the Nordic Musculoskeletal Questionnaire (NMQ), respectively.</p> Results <p>Waist-to-hip ratio (WHR) ≥ 0.9 was present in 26% of participants and was associated with higher CRP levels (<i>p</i> = 0.005). Percent of body fat and WHR ≥ 0.9 were independent predictors of CRP in adjusted models (β = 0.053, <i>p</i> = 0.010 and β = 0.74, <i>p</i> = 0.029, respectively). No significant associations were found between CRP and musculoskeletal abnormalities with MSP across the assessed regions. Forward head posture was associated with higher WHR (<i>p</i> = 0.029), and low back pain was more frequent in children with higher WHR (<i>p</i> = 0.028) and lower physical activity (<i>p</i> = 0.044).</p> Conclusion <p>WHR and overall adiposity are key drivers of systemic inflammation in children with obesity, while musculoskeletal symptoms are mainly influenced by age, fat distribution, and activity levels. The causes of pain in these children are multifactorial and require further research.</p>