Purpose of Review <p>This review explores clonidine as a potential treatment for agitation across various clinical contexts, focusing on its application in patients with limited cognitive reserve, hyperactive delirium, or conditions where standard treatments may exacerbate underlying symptoms, such as Parkinsonism. The review evaluates the pharmacological properties, efficacy, and practical considerations for using clonidine in managing agitation, including its role in other psychiatric and medical conditions.</p> Recent Findings <p>Clonidine, a centrally acting alpha-2 adrenergic agonist, reduces norepinephrine release, leading to sedation, anxiolysis, and analgesia without significant respiratory depression. Recent studies and case reports highlight its utility in managing agitation, ADHD, autism spectrum disorders, dementia, and hyperactive delirium. Clonidine has demonstrated advantages over antipsychotics in preserving cognitive function and minimizing delirium duration. Additionally, it shows promise in treating PTSD-related nightmares and as an adjunct in anesthesia and analgesia.</p> Summary/Takeaway <p>Clonidine offers a well-tolerated, cost-effective alternative to antipsychotics for managing agitation, particularly in vulnerable populations. Its diverse applications, favorable safety profile, and minimal impact on Parkinsonism make it a valuable tool in psychiatry and medicine. Further research is needed to refine dosing protocols and expand its indications in managing agitation and related symptoms.</p>