Background: This retrospective cohort study aimed to examine the interaction effect between puberty stage and weight status on individual and clustering of cardiometabolic risk factors (CMRFs) among Mexican American children and adolescents. A total of 333 children and adolescents (aged 8-18 years) enrolled in the Cameron County Hispanic Cohort (CCHC) from 2014 to 2020 were included in the study. Methods: CCHC is a longitudinal, randomly recruited cohort based on the United States Census tracts/blocks of Mexican Americans living on the Texas-Mexico border. Individual CMRFs, including high blood pressure, central obesity, hypertriglyceridemia, low high-density lipoprotein cholesterol, and insulin resistance (IR) were assessed. Clustering of CMRFs is defined as the presence of three or more individual CMRFs. Puberty stages were assessed using the Tanner criteria. Multivariable logistic regressions were conducted to assess the association of puberty, weight status, and the interaction of the two main exposures with individual and clustering of CMRFs. Results: We observed that weight status had a dominant effect on all CMRF measures. The effect was especially prominent on central obesity and clustering of CMRFs. There were 95.4% of children with central obesity and 98.4% of those with clustering of CMRF were either overweight or obese. Entering puberty was associated with an increased risk of having IR [Tanner stage 2 vs. 1: odds ratio (OR) = 3.25, 95% confidence interval (95% CI) 1.28-8.27; Tanner stage 3 vs. 1: OR = 3.50, 95% CI 1.45-8.46] and hypertriglyceridemia (Tanner stage 2 vs. 1: OR = 2.67, 95% CI 1.11-6.45). However, the effects were not observed among those reaching the end of puberty (Tanner stage 4 and 5). Conclusions: A significant interaction effect between weight status and puberty was not detected on any individual CMRF and in the clustering of CMRFs. Other factors positively associated with individual CMRFs, especially IR, were being female and having a family history of diabetes.