Attention deficit/hyperactivity disorder (ADHD) is a common neurobehavioral and neuropsychiatric disorder in school-age children, and recent studies provide evidence implicating the metabolic abnormalities of dopamine (DA) for its pathophysiology. Methylphenidate, a kind of psychostimulant, is widely used in the treatment of ADHD, but some patients do not respond to it or cannot bear its side effects. As a traditional Chinese medicine preparation, Ningdong granule (NDG) has been used in the treatment of ADHD for several years in China. However, a systematical pharmacological study on its safety and mechanism still remains obscure. This paper aims to evaluate the efficiency, safety, and possible mechanism of NDG on ADHD children compared to methylphenidate. Seventy-two ADHD children were recruited to perform an 8-week, randomized, methylphenidate-controlled, doubled-blinded trial. The subjects were equally assigned to two groups receiving either NDG 5 mg/kg/day or methylphenidate 1 mg/kg/day for 8 weeks. The efficiency was assessed by the Teacher and Parent ADHD Rating Scales every 2 weeks for a total of 8 weeks. The side effects were recorded during the study. Blood, urine, and stool routine samples, liver and renal function test, and DA and homovanillic acid (HVA) concentration in sera were tested at the beginning and end of the trial. NDG ameliorated ADHD symptoms after an 8-week medication with fewer side effects compared to methylphenidate (P < 0.05). The result also showed NDG to be safe and tolerable for ADHD children as monitored by the blood, urine, and stool analysis and liver and renal function for 8 weeks (P < 0.05). Moreover, the level of HVA in sera increased in NDG-treated group (P < 0.05), while the content of DA had no significant change during the study. An analysis of Pearson correlation coefficients also showed that the increased content of HVA in sera was associated with the improved scores of Teacher and Parent ADHD Rating Scales. Compared to methylphenidate, NDG is effective and safe for ADHD children in the short term, increases the HVA concentration in sera to regulate DA metabolism, and promises to be an alternative medication, safely and effectively.