AbstractBackgroundsPrevious studies have demonstrated that both serum lipid levels and sex are crucial factors associated with individual cognition. However, the impact of sex and serum lipid interaction effects on the brain and cognition remains largely unknown. This study aimed to explore the underlying neural mechanisms among sex, serum lipids, and cognition using large‐scale brain networks.MethodsResting‐state functional MRI data were collected from 157 young healthy adults. Independent component analysis was used to examine large‐scale inter‐ and intra‐network functional connectivity (FCs). Peripheral venous blood samples were collected to measure serum lipid levels. The three‐back task was employed to assess cognition (i.e., working memory). General linear model, correlation, and mediation analyses were conducted to examine the interaction effects of sex and serum lipids on large‐scale brain networks and their relationship with working memory.ResultsWe found that inter‐network connectivity with the executive control network at its core was more susceptible to sex and triglyceride interaction effects. The intra‐network connectivity in the dorsal attention networks (DANs), lateral visual networks, and anterior default mode networks was influenced by the interaction effects of sex and total cholesterol (TC)/low‐density lipoprotein cholesterol. Specifically, correlations between serum lipids and affected brain networks were found to be sex‐specific. In addition, higher intra‐network FC in the right inferior parietal (R‐IPL) of the DAN correlated with a longer three‐back reaction time in females. More importantly, the relationship between serum TC levels and three‐back reaction time was mediated by intra‐network connectivity in the R‐IPL of the DAN.ConclusionsOur findings describe the impact of sex and serum lipid interaction effects on large‐scale brain networks, as well as on cognitive function. Our data suggest that sex‐specific usage of serum lipids or brain networks would be beneficial for monitoring and therapy in dyslipidemia‐related cognition decline.