Primary Sjögren's syndrome (pSS) is an autoimmune disease that primarily affects exocrine glands and is characterized by sicca syndrome and systemic manifestation. Mounting evidence indicates that circadian clocks are involved in the onset and progression of autoimmune diseases, including rheumatic arthritis, multiple sclerosis, and systemic lupus erythematosus. However, few studies have reported the expression of clock genes in pSS. There is no ideal therapeutic method for pSS, the management of pSS is mainly palliative, aims to alleviate sicca symptoms. Melatonin is a neuroendocrine hormone mainly secreted by the pineal gland that plays an important role in the maintenance of the circadian rhythm and immunomodulation. Hence, this study aimed to analyse the circadian expression profile of clock genes in pSS, and further evaluate the therapeutic potential of melatonin in pSS. We discovered a distinct clock gene expression profile in the salivary glands of pSS patients and pSS animal model. More importantly, melatonin administration improved the hypofunction of the salivary glands, inhibited inflammatory development, and regulated clock gene expression in animal model of pSS. Our study suggested that the pathogenesis of pSS might correlate with abnormal expression of circadian genes, and that melatonin might be a potential candidate for prevention and treatment of pSS.