Background: Metabolic syndrome (MetS) is thought to promote biological aging, which might lead to cardiovascular and aging-related complications. This large-scale study investigated longitudinal relationships between MetS, its components, and cellular aging markers: leukocyte mitochondrial DNA copy number (mtDNAcn) and telomere length (TL). Methods: We included 989 participants from the Coronary Artery Risk Development in Young Adults Study. MtDNAcn [study year (Y) 15, Y25] and TL (Y15, Y20, Y25) were measured via quantitative polymerase chain reaction. MetS components [waist circumference, triglycerides, high-density lipoprotein (HDL) cholesterol, systolic blood pressure, and fasting glucose] were determined (Y15, Y20, Y25). Generalized estimated equation and linear regression models, adjusting for sociodemographics and lifestyle, were used to examine associations between MetS and cellular aging at all time points, baseline MetS and 10-year changes in cellular aging, baseline cellular aging and 10-year changes in MetS, and 10-year changes in MetS and 10-year changes in cellular aging. Results: MtDNAcn and TL were negatively associated with age [mtDNAcn unstandardized β (B) = 24.76; P < 0.001; TL B = -51.53; P < 0.001] and positively correlated (r = 0.152; P < 0.001). High triglycerides were associated with low mtDNAcn and low HDL cholesterol with short TL. Greater Y15 waist circumference (B = -7.23; P = 0.05), glucose (B = 013.29; P = 0.001), number of metabolic dysregulations (B = -7.72; P = 0.02), and MetS (B = -28.86; P = 0.006) predicted greater 10-year decrease in mtDNAcn but not TL. The 10-year increase in waist circumference was associated with 10-year telomere attrition (B = -27.61; P = 0.04). Conclusions: Our longitudinal data showed that some metabolic dysregulations were associated with mtDNAcn and TL decreases, possibly contributing to accelerated cellular aging but not the converse.