Background: Infectious disease is an increasing threat to patients with systemic lupus erythematosus (SLE); however, the long-term outcome in critically ill septic patients with SLE remains unclear, and we aimed to address the impact of SLE on 5-year survival in critically ill septic patients. Methods: We used the 2003–2017 nationwide data with 825,556 patients with sepsis in Taiwan. We identified lupus cases with sepsis that required admission to the intensive care unit and mechanical ventilation and selected controls matched (1:4) for age, sex, and index-year. Conditional logistic regression analysis was used to determine risk factors for mortality risk and shown as odds ratios (HRs) with 95% confidence intervals (CIs). Results: A total of 513 SLE-sepsis patients and 2052 matched non-SLE septic individuals were enrolled. The mortality rate was higher in the SLE group (38.5 per 100,000 person-year) than that in the non-SLE group (13.7 per 100,000 person-year), with an IRR of 2.8 (95% CI, 2.5–3.2). We found that SLE was independently associated with a high mortality rate after adjusting relevant variables (HR 1.47, 95% CI 1.27–1.77). In addition to SLE, a higher age (HR 1.02, 95% CI 1.02–1.02), more comorbidities, and receiving prednisolone equivalent dose higher than 5 mg/day (HR 1.55, 95% CI 1.27–1.90), methotrexate (HR 2.19, 95% CI 1.61–2.99), and immunosuppressants (HR 1.45, 95% CI 1.22–1.74) were also independent risks for mortality. Conclusions: We identified that SLE affects the long-term mortality in critically ill septic patients, and more studies are warranted for the underlying mechanism.