Spinal pain has been previously linked with cardiovascular disease risk factors in children. This study investigated the prospective associations between cardiovascular disease risk factors and non-traumatic spinal pain occurrences in children, and examined the moderating role of sex and health-related physical activity in these relationships. We used prospective data from the Childhood Health, Activity, and Motor Performance School Study Denmark (CHAMPS Study-DK). The exposure variables were a clustered cardiovascular risk score and homeostasis assessment model-estimated insulin resistance (HOMA-IR) score collected in 2008 and 2010. The spinal pain outcome comprised the number of weeks of non-traumatic spinal pain from 2008-2010 and 2010-2012. Potential confounders included age, sex, and time spent in moderate-to-vigorous intensity physical activity. We constructed age-adjusted mixed negative binominal regression models to investigate the prospective associations of cardiovascular disease risk factors and non-traumatic spinal pain, while considering the potential moderating roles of sex and physical activity in these relationships. Girls with low HOMA-IR scores and boys with low clustered cardiovascular disease risk scores, who engaged in higher levels of moderate-to-vigorous physical activity, reported more weeks of spinal pain, compared to girls with high HOMA-IR scores (p = 0.001) and boys with high clustered cardiovascular disease risk scores (p = 0.024). whereas boys with higher clustered cardiovascular disease risk who had less time in moderate-to-vigorous physical activity reported more weeks of spinal pain than boys with low clustered cardiovascular disease risk score (p = 0.024). Our results show that cardiovascular disease risk factors are related to future occurrences of non-traumatic spinal pain. However, these relationships appear complex and dependent on the nature of the interactions with sex and physical activity.