Aims Our cost of illness study aimed to provide an estimate of the burden related to systemic lupus erythematosus (SLE) in the Mexican context. Methods Our model was used to simulate the resource utilization and economic consequences over a period of 5 years for patients with SLE in Mexico. The model simulated four health states—three phenotypes of SLE, including mild, moderate, and severe states, and death. Clinical parameters were retrieved from the literature. Resource utilization in our model represents the most common practice in the Mexican healthcare system. These include disease management, transient events (e.g. infections, flares, and complications due to SLE-related organ damage), and indirect costs. Direct non-medical costs were not considered. One-way sensitivity analysis was performed. Results The number of targeted Mexican SLE patients was 57,754. The numbers of SLE patients diagnosed with mild, moderate, and severe phenotypes were 8,230, 44,291, and 5,233, respectively. Disease management costs, including the treatment of each phenotype and disease follow-up, were MXN 4 billion ($ 415 million); the costs of transient events (infections, flares, and consequences of SLE-related organ damage) were MXN 5 billion ($ 478 million). Productivity loss costs among adult employed Mexican patients with SLE were estimated at MXN 17 billion ($ 1.6 billion). The total SLE cost in Mexico over 5 years from the payer and societal perspectives is estimated at MXN 9 billion ($ 893 million) and 26 billion ($ 2.5 billion), respectively. Over 5 years, the costs per patient per year from the payer and societal perspectives were MXN 32,131($ 3,095) and MXN 91,661($ 8,830), respectively. Conclusion The findings pointed out the substantial economic burden associated with SLE, including the costs of disease progression and SLE transient events, such as flare-ups, infections, and organ damage, in addition to productivity loss due to work capacity impairment.