To examine the association between endometriosis and the risk of systemic lupus erythematosus (SLE), this nationwide, population-based, retrospective cohort study was conducted based on National Health Insurance Research Database in Taiwan. Endometriosis (N = 16,758) and non-endometriosis (N = 16,758) groups were identified by matching baseline characteristics and comorbidities. Student's t-tests and the Kaplan-Meier estimator were utilized to estimate the hazard ratio (HR) and cumulative probability of SLE in the two groups. The endometriosis group showed a significantly higher incidence density rate (0.3 vs. 0.1 per 1000 person-years) and hazard ratio in SLE group (adjusted HR [aHR], 2.37; 95% confidence interval [CI] 1.35-4.14) compared to the non-endometriosis group. Subgroup analysis revealed that patients with endometriosis between 30 and 45 years of age, or were non-steroidal anti-inflammatory drug users, or were hormonal medications-free participants, had higher risks of SLE. For patients with endometriosis, surgical intervention did not significantly impact on the risk of SLE. Our results demonstrated an increased risk of SLE in patients with endometriosis. Clinicians should be aware of this association when managing patients with endometriosis or SLE.