Background and aim <p>Obstructive sleep apnea (OSA) and metabolic dysfunction-associated steatotic liver disease (MASLD) are frequently encountered in patients with obesity. The interplay of OSA, MASLD and obesity is unknown. We aimed to elucidate the role of OSA in the relationship between the severity of obesity and MASLD.</p> Methods <p>We enrolled 552 patients intending to undergo sleeve gastrectomy (SG) from January 2020 to August 2023. Biochemical parameters were detected, and sleep breathing conditions were measured before SG. Liver biopsy was performed during SG. Multiple linear regressions and logistic regressions were performed to determine the effect of OSA on MASLD. Multiple mediation analyses were conducted to elucidate the mediating role of OSA in the obesity-MASLD association.</p> Results <p>OSA severity was independently associated with liver histology, including steatosis score [odds ratio (OR) = 1.424, 95% confidence interval (CI) 1.027–1.975, p = 0.034], nonalcoholic fatty liver disease activity score (OR = 1.459, 95% CI 1.059–2.008, p = 0.021), and fibrosis stage (OR = 1.464, 95% CI 1.024–2.092, p = 0.037) after multivariable adjustment. Multiple mediation analyses revealed that mean pulse oxygen saturation (MSpO₂) mediated the associations of body mass index (BMI) with hepatic steatosis and metabolic dysfunction-associated steatohepatitis (MASH). Furthermore, high-density lipoprotein cholesterol (HDL-C) acted as a moderator of the indirect effect of BMI on hepatic steatosis via MSpO₂ (Index of moderated mediation = 0.255, 95% CI 0.077–0.573, p = 0.042).</p> Conclusion <p>OSA was independently associated with hepatic steatosis and MASH in patients with obesity. MSpO₂ could serve as a mediator in the obesity-MASLD association, and HDL-C exhibited a significant moderating role in this pathway. These findings highlight the necessity for the management of OSA to protect against MASLD in patients with obesity.</p>