The role of chloroquine (CQ) and hydroxychloroquine (HCQ) in the management of dry eye disease is still unclear. This systematic review and meta-analysis investigates the efficacy and feasibility of CQ and HCQ in patients with dry eye disease. In February 2023, PubMed, Embase, Google Scholar, and Web of Science were accessed. Data from 462 patients (mean age 54.4 ± 2.8 years) were collected. Compared to baseline, the tear breakup time (p< 0.0001) and Schirmer I test (p< 0.0001) were significantly increased, and the Ocular Surface Disease Index (OSDI,p< 0.0001) and corneal staining (p< 0.0001) were significantly decreased at the last follow-up in the CQ/HCQ group. At the last follow-up, the OSDI was significantly lower in the CQ/HCQ group compared to the control group (p< 0.0001). Corneal staining was significantly greater in the control group compared to the CQ/HCQ group (p< 0.0001). The Schirmer I test showed no significant difference between the groups (p= 0.2). Altogether, CQ and HCQ improved the symptoms and signs of dry eye disease.