BACKGROUND: Sepsis remains a significant health challenge in ICU, with septic shock requiring meticulous glycaemic management due to metabolic dysregulation. Existing research highlights the detrimental effects of both hyperglycaemia and hypoglycaemia on septic patient outcomes, emphasizing the need for effective glycaemic control. Despite extensive studies, optimal glycaemic targets in septic shock patients remain contentious and unclear, necessitating further research. AIM: Our study aims to identify optimal glycaemic targets for patients in septic shock by analysing time-series blood glucose data. STUDY DESIGN: This retrospective observational study utilized the MIMIC-IV database, encompassing ICU patients diagnosed with septic shock from 2008 to 2019. We extracted time-series blood glucose data and applied the Stineman interpolation to achieve a standardized resolution. The primary analysis involved calculating the time-weighted average blood glucose (TWA-BG) and examining its relationship with 28-day mortality using a restricted cubic spline model within a Cox regression framework. Sensitivity analyses with multiple models and subgroup analyses were used to reveal the robustness of the results. RESULTS: From 34 677 identified septic patients, 11 375 met the inclusion criteria. The optimal TWA-BG range, associated with the lowest 28-day mortality risk, was determined to be 105 to 131 mg/dL. Patients within this range exhibited significantly lower mortality rates compared to those with higher or lower TWA-BG levels. Sensitivity analyses confirmed these findings, indicating robustness across various subgroups and analytical models. CONCLUSIONS: Our findings suggest that maintaining TWA-BG levels between 105 and 131 mg/dL minimizes the risk of 28-day, ICU, and in-hospital mortality in patients with septic shock. RELEVANCE TO CLINICAL PRACTICE: The results provide evidence-based guidance for ICU nursing interventions, advocating for a precise TWA-BG range to be maintained for septic shock patients, thus potentially setting new benchmarks for glycaemic control in critical care settings.