Objective <p>We aim to investigate the association between serum osmolality and the risk of developing delirium in septic patients.</p> Methods <p>Adult septic patients meeting the Sepsis-3 definition were included. Delirium was screened according to the Confusion Assessment Method for the ICU (CAM-ICU) tool. Patients lacked of serum osmolality results and those with delirium prior to sepsis occurrence were excluded. The association between osmolality and delirium was visualized using both restricted cubic splines (RCS) and local weighted scatter plot smoothing (LOWESS) methods. Logistic regression, subgroup and sensitivity analysis were performed to determine the predictive value of osmolality on delirium.</p> Results <p>A total of 17,171 septic patients were included. A U-shaped pattern was observed between serum osmolality and delirium risk (<i>P</i> for non-linear &lt; 0.001). Compared with intermediate range (286–301 mmol/L), patients in the low and high osmolality groups had an increased percentage of delirium. Compared with intermediate osmolality, low and high osmolality could increase the risk of delirium by 21.6-34.5% (OR 1.216–1.345) and 18.4-53.3% (OR 1.184–1.533). All subgroups analysis supported that abnormal osmolality is an independent risk factor for delirium (OR &gt; 1), and a more significant association was found in SOFA &lt; 6 subgroup. In sensitivity analysis, the presence of comorbidities made no influence on this U-shaped relationship. After balancing the baseline information by propensity score matching (PSM), patients in the intermediate range still had a lower incidence of delirium.</p> Conclusion <p>There was a U-shaped association between serum osmolality and the risk of sepsis-associated delirium. Further high-quality research is needed to verify our findings.</p> Clinical trial number <p>Not applicable.</p>