Objectives The aim of this study to compare the clinic efficacy and effects of osmotic release oral system-methylphenidate and atomoxetine on executive function in children and adolescents with attention deficit hyperactivity disorder by a open-label, prospective, randomized controlled trial. Methods The study was performed by 95 cases between ages 6 and 12 years who were diagnosed as attention-deficit/hyperactivity disorder (ADHD) and also 40 control individuals. In this study, Conners' Teacher Rating Scale (CTRS) was used in order to evaluate the efficacy of the treatment. Executive functions were assessed by the performance-based neuropsychological tests and ecological behavioral rating scales. Stroop test, cancellation test, and serial digit learning test were applied to performance based neuropsychological tests. Behavior Rating Inventory of Executive Function tests (BRIEFs) were used as behavioral assessment scales. Results Among the ADHD groups, a reduction of over 40% in the CTRS subtest scores used to evaluate the efficacy of the treatment was considered to be an improvement, and no significant difference was found for both drugs. Both Osmotic Release Oral System-Methylphenidate Hydrochloride (OROS-MPH) and atomoxetine (ATX) significantly improved scores in neuropsychological tests. Conclusion Atomoxetine and OROS-MPH treatments have shown similar efficacy in clinical recovery and improvement on executive functions. However, disturbances in executive functions observed in children with ADHD are persistent despite treatment, when compared with the control group.