Abstract: Objective To evaluate the efficacy of clonidine extended-release tablets in the treatment of children with attention deficit hyperactivity disorder (ADHD) comorbid with tic disorder and to assess their effects on neuroimmune function. Methods A total of 120 children with ADHD comorbid with tic disorder, who were admitted to the Affiliated Hospital of Xuzhou Medical University from January 2024 to December 2024, were enrolled. They were randomly divided into two groups (n=60): a clonidine extended-release group (observation group) and a methylphenidate hydrochloride extended-release group (control group). The clinical efficacy, Conners' Parent Rating Scale (CPRS) scores, Yale Global Tic Severity Scale (YGTSS) scores, peripheral blood T lymphocyte subsets, neurotransmitter levels, and adverse events were analyzed by the t-test, chi-square test, and rank-sum test. Results The total effective rate in the observation group was significantly higher than that in the control group (P<0.05). The observation group showed significantly lower scores in conduct problems, learning problems, psychosomatic disorders, hyperactivity-impulsivity, anxiety index, and hyperactivity index (P<0.05). Moreover, their motor tic score, vocal tic score, and total YGTSS score were also significantly lower in the observation group (P<0.05). After treatment, both groups exhibited increases in total T lymphocytes, helper T lymphocytes, and Th/Ts ratios, and decreases in suppressor T lymphocytes compared with those before treatment; these changes were more pronounced in the observation group (P<0.05). The levels of peripheral blood serotonin (5-HT), norepinephrine (NE), and dopamine (DA) decreased in both groups after treatment, with a more significant reduction in the observation group (P<0.05). Conclusions Clonidine extended-release tablets effectively alleviate attention deficits, hyperactivity/impulsivity, and tic symptoms in children with ADHD comorbid with tic disorder. The therapeutic mechanism may be related to modulation of immune function and improvement of neurotransmitter imbalance.