Background. The association of genetic and dietary factors with occurrence and progression of chronic diseases such as metabolic syndrome (MetS) has long been addressed but there is a lack of evidence for complex interrelationships, including direct and indirect effects of these variables. Hence, this study is aimed at evaluating the mediating role of glycemic indices in the association of melanocortin‐4 receptor (MC4R) rs17782313 polymorphism, sociodemographic, and psychological factors with the risk of MetS in obese adults using structural equation modeling. Methods. We performed a cross‐sectional analysis of data from 287 apparently healthy adults. Dietary glycemic index (GI) and glycemic load (GL) were calculated from a validated 147‐item food frequency questionnaire (FFQ). MC4R s17782313 genotypes were determined by polymerase chain reaction‐restriction fragment length polymorphism (PCR‐RFLP) method. Structural equation modeling was used to explore direct and indirect effects of genetic and nongenetic factors on MetS. Results. MC4R gene variant was directly associated with the risk of MetS (B = 0.010; P = 0.023). On the other hand, this variant was found to be indirectly and positively associated with LDL‐C (B = 6.589; P = 0.042) through mediatory effects of GI and GL. Moreover, GI and GL also mediated indirect positive effects of sex and age on LDL‐C (B = 3.970; P ≤ 0.01; B = 0.878; P ≤ 0.01, respectively) and HDL (B = 2.203; P ≤ 0.01; B = 0.129; P ≤ 0.01, respectively). MC4R rs17782313 polymorphism had positive effects on GI (B = 1.577; P ≤ 0.01) and GL (B = 1.235; P ≤ 0.01). Conclusion. Our data may state a hypothesis of the mediating effect of quantity and quality of carbohydrates consumed in relationship between genetic susceptibility to obesity and cardiometabolic risk factors. Further analyses should be carried out in high‐quality cohort studies in order to confirm the findings.