Background Systemic lupus erythematosus (SLE) is a multisystem autoimmune disease characterized by various clinical manifestations. Despite efforts to improve outcomes, mortality rates remain high, and certain disparities, including gender, may influence prognosis and mortality rates in SLE. This study aims to examine the gender disparities in outcomes of SLE hospitalizations in the US. Methods We conducted a retrospective analysis of the Nationwide Inpatient Sample (NIS) database between 2016 and 2020. The NIS database is the largest publicly available all-payer database for inpatient care in the United States, representing approximately 20% of all hospitalizations nationwide. We selected every other year during the study period and included hospitalizations of adult patients (≥18 years old) with a primary or secondary diagnosis of SLE using International Classification of Diseases, Tenth Revision (ICD-10) codes. The control population consisted of all adult hospitalizations. Multivariate logistic regression was used to estimate the strength of the association between gender and primary and secondary outcomes. The regression models were adjusted for various factors, including age, race, median household income based on patients' zip codes, Charlson comorbidity index score, insurance status, hospital location, region, bed size, and teaching status. To ensure comparability across the years, revised trend weights were applied as the healthcare cost and use project website recommends. Stata version 17 (StataCorp LLC, TX, USA) was used for the statistical analyses, and a two-sided P-value of less than 0.05 was considered statistically significant. Results Among the 42,875 SLE hospitalizations analyzed, women accounted for a significantly higher proportion (86.4%) compared to men (13.6%). The age distribution varied, with the majority of female admissions falling within the 30- to 60-year age range, while most male admissions fell within the 15- to 30-year age category. Racial composition showed a slightly higher percentage of White Americans in the male cohort compared to the female cohort. Notably, more Black females were admitted for SLE compared to Black males. Male SLE patients had a higher burden of comorbidities and were more likely to have Medicare and private insurance, while a higher percentage of women were uninsured. The mortality rate during the index hospitalization was slightly higher for men (1.3%) compared to women (1.1%), but after adjusting for various factors, there was no statistically significant gender disparity in the likelihood of mortality (adjusted odds ratio (aOR): 1.027; 95% confidence interval (CI): 0.570-1.852; P=0.929). Men had longer hospital stays and incurred higher average hospital costs compared to women (mean length of stay (LOS): seven days vs. six days; $79,751 ± $5,954 vs. $70,405 ± $1,618 respectively). Female SLE hospitalizations were associated with a higher likelihood of delirium, psychosis, and seizures while showing lower odds of hematological and renal diseases compared to men. Conclusion While women constitute the majority of SLE hospitalizations, men with SLE tend to have a higher burden of comorbidities and are more likely to have Medicare and private insurance. Additionally, men had longer hospital stays and incurred higher average hospital costs. However, there was no significant gender disparity in the likelihood of mortality after accounting for various factors.