To examine the association between psychological resilience and cognitive function and investigate the role of acute inflammation as an effect modifier. Total 7535 people from the Cardiovascular and Metabolic Disease Etiology Research Center (CMERC), aged ≥ 50 years and residing in areas near Seoul, South Korea, were included in this cross-sectional analysis. Stressful life events in the past 6 months were gauged by the Life Experience Survey, and current depression symptoms were analyzed with the Beck Depression Inventory-II. Participants were categorized into the following four groups according to their past experience and depression status: reference, resilient, reactive depression, and vulnerable depression. Cognitive function was evaluated using the mini-mental state examination (MMSE). The level of high-sensitivity C-reactive protein (hsCRP) was measured from blood samples. A generalized linear model was used. Upon adjusting for socio-demographic factors, comorbidity, and lifestyle factors, the final model was stratified with the highest quartile of the hsCRP level by sex. Compared to the reference group, the resilient group showed higher MMSE, which was also significant in women (adj-β = 0.280, p-value < 0.001). Vulnerable depression group showed a significantly lower MMSE (adj-β =  - -0.997, p-value 0.002), especially in men. This pattern seemed to be limited to the low hsCRP subgroup. We provided evidence from the largest Korean population used to evaluate the association between psychological resilience and cognition, which was more prominent in low inflammatory status. Psychological resilience was associated with a lower likelihood of cognitive deficit in women. This pattern was modulated by inflammatory status.