Clinical observations have shown that cases of stroke or thromboembolism are not uncommon even in the absence of atrial fibrillation, suggesting that atrial fibrillation is a delayed marker of atrial thrombus formation. Atrial cardiomyopathy (ACM) is a pathophysiological concept characterized by atrial substrate and functional abnormalities closely associated with atrial myopathy, atrial enlargement, and impaired ventricular diastolic function. It is an independent factor for thromboembolic stroke, increasing the risk of serious complications such as atrial fibrillation, heart failure, and sudden cardiac death. ACM is likely to be a potential cause of embolic stroke, especially cryptogenic stroke, and early identification of patients at high thromboembolic risk is essential to guide anticoagulation therapy. Although the pathogenesis of ACM has not been fully elucidated, prospective mechanism-based studies have revealed the important role of activated cardiac immune cells along with inflammatory responses, oxidative stress, and other factors in its progression. Exploring the role of immune regulation in the pathogenesis of ACM provides new insights into the underlying mechanisms of cerebrovascular events of cardiac thromboembolic origin. This review summarizes the mechanisms by which immune regulation is involved in the progression of ACM and provides useful insights for future clinical diagnosis and treatment.