The prevalence of obesity among children and adolescents with autism spectrum disorder (ASD) is higher than that among typically developing children and adolescents. However, very few studies have explored the genetic factors associated with obesity in children and adolescents with ASD. Thus, the aim of this study was to examine the associations between 3-hydroxy-3-methylglutaryl-coenzyme A reductase (HMGCR) gene polymorphisms and obesity among children and adolescents with ASD. The study participants consisted of 33 children and adolescents with ASD and 271 age- and sex-matched typically developing controls. We compared the metabolic traits (body mass index, blood pressure, triglyceride, high-density lipoprotein, and fasting glucose levels) between the ASD and control group. Furthermore, we assessed the genotypes of rs12654264 in the HMGCR gene within the participants with ASD, and compared metabolic traits among the different allele subgroups. The mean body mass index (BMI) and triglyceride level of the ASD group were significantly higher than those of the control group. Within the ASD group, the triglyceride level of participants with rs12654264-T alleles was significantly higher than that of participants with A-alleles. A pattern of increasing values in the BMI and fasting glucose was also observed in participants with T allele. This is the first study to show that obesity in children and adolescents with ASD is associated with the cholesterol synthesis pathway. Future studies are needed to further clarify the molecular mechanisms by which the HMGCR gene influences metabolic traits.