Sugar intake, particularly fructose, is implicated as a factor contributing to insulin resistance via hepatic de novo lipogenesis (DNL). A nine-day fructose reduction trial, controlling for other dietary factors and weight, in children with obesity and metabolic syndrome, decreased DNL and mitigated cardiometabolic risk (CMR) biomarkers. Ceramides are bioactive sphingolipids whose dysregulated metabolism contribute to lipotoxicity, insulin resistance, and CMR. We evaluated the effect of fructose reduction on ceramides and correlations between changes observed and changes in traditional CMR biomarkers in this cohort. Analyses were completed on data from 43 participants. Mean weight decreased (−0.9 ± 1.1 kg). The majority of total and subspecies ceramide levels also decreased significantly, including dihydroceramides, deoxyceramides and ceramide-1-phoshates. Change in each primary ceramide species correlated negatively with composite insulin sensitivity index (CISI). Change in deoxyceramides positively correlated with change in DNL. These results suggest that ceramides decrease in response to dietary fructose restriction, negatively correlate with insulin sensitivity, and may represent an intermediary link between hepatic DNL, insulin resistance, and CMR.