Introduction Despite the well-established association between antipsychotics and metabolic adverse effects in psychiatric disorders, the variable influence of long-term and off-label antipsychotic medication on behavioral disorders has not been investigated in detail. Objective To clarify the impact of antipsychotic use on challenging behavior (CB) and neuropsychiatric symptoms (NPS), we evaluated the clinical findings and cardiometabolic effects in individuals with intellectual disability (ID) hospitalized in our residential facility for profoundly disabled patients. Patients and methods A total of 130 individuals hospitalized in our residential facility were retrospectively investigated and divided into two groups - individuals with and without CB and NPS. Antipsychotics (first- and second-generation antipsychotics) are prescribed to all individuals in the CB and NPS-positive ID group. Conversely, antipsychotics were not prescribed to any individuals in the CB- and NPS-negative ID groups. To investigate the cardiometabolic effects of antipsychotics, the following metabolic parameters were measured: body weight (BW), total calorie intake per day, body mass index (BMI), blood pressure, serum lipid levels (total cholesterol, high-density lipoprotein cholesterol, and triglyceride), and corrected QT interval (QTc) of electrocardiogram (ECG). The etiology of disabilities, level of ID, severity of motor disability, and presence or absence of epilepsy were also examined. Results Two main results were derived: (1) Autism spectrum disorder was the most predominant etiology in individuals with CB and NPS who were prescribed antipsychotics, and (2) the mean values of metabolic parameters were all normal in both medicated and nonmedicated individuals, but the total calorie intake was significantly higher in individuals who were prescribed antipsychotics. Conclusions Our investigation demonstrated that in individuals with an adequate energy intake, most metabolic parameters can be maintained within normal limits. We suggest that body weight control is the primary step in avoiding the cardiometabolic adverse effects of antipsychotics in intellectually disabled individuals with CB and NPS.