Background <p>Children and adolescents with chronic physical conditions have an increased probability of mental health problems, which may be partly attributed to the variations in play behavior<b>.</b> This study explores the associations between having a chronic physical condition, play behavior, and having mental health problems.</p> Methods <p>Data from the Generation R Study were analyzed, a population-based, prospective cohort in the Netherlands. Chronic physical conditions were typically identified before six years of age. Play behavior was assessed at ages 6 and 10. Mental health problems were measured with the Child Behavior Checklist at 14 years of age. Logistic, ranked-order, and linear regression analyses were used to examine direct associations, and mediation analyses were used to investigate indirect paths. <i>P</i> values were false discovery rate adjusted.</p> Results <p>Of the 4043 included participants, 691 (17%) had a chronic physical condition. Having a chronic physical condition was associated with more mental health problems and limited activity at the age of six years. Playing sports and engaging in social interactions at age 10 were related to fewer mental health problems at age 14. Limited activity mediated the relationship between having a chronic physical condition and mental health problems (social: mediated_proportion = 8.33%, 95% CI = 2.02%; 15.7%, <i>P</i>_adj &lt; 0.001; physical: mediated_proportion = 7.72%, 95% CI = 1.73%; 19.1%, <i>P</i>_adj = 0.040).</p> Conclusions <p>Health-related limitations in social and physical activities mediate the relationship between having a chronic physical condition and mental health problems in children. Participation in social and physical activities early in life may be crucial for the mental well-being of children with a chronic physical condition.</p> Graphical abstract <p></p>