Background: Fluid resuscitation is a standard intervention for patients with sepsis, however, the ideal timing for initiating fluid deresuscitation has not been well established. This study examines the prognostic impact of early versus delayed initiation of loop diuretics in patients with sepsis. Methods: Data for this analysis were obtained from the Medical Information Mart for Intensive Care IV (MIMIC-IV) database. Patients diagnosed with sepsis were categorized into two groups based on the timing of loop diuretic administration: an early group (within 48 hours of diagnosis) and a late group (after 96 hours). Results: A total of 8,518 patients with sepsis were included in this study. Of these, 4,485 patients received loop diuretics within the first 48 hours (early group), while the remaining 4,033 patients received loop diuretics after 96 hours (late group). In the early group, 75% of patients required mechanical ventilation, which was significantly lower than the 85.6% in the late group (P<0.001). However, the early group demonstrated a significantly higher 28-day mortality rate compared to the late group (832/4,485 vs. 679/4,033, P=0.03). Cox regression analysis indicated that the early initiation of diuretics was associated with an increased 28-day mortality rate [hazard ratio (HR) =2.590, 95% confidence interval (CI): 2.325-2.884, P<0.001]. After adjusting for the proportional hazards assumption, the corrected HR was recalculated as exp[3.55-1.20 x ln(t)]. Propensity score matching (PSM) resulted in two well-matched groups of 1,882 patients each. Post-matching analysis revealed that the early group continued to exhibit significantly higher 28-day and in-hospital mortality (P<0.001) along with a significantly higher incidence of stage 3 acute kidney injury (AKI) (8.1% vs. 5.7%, P=0.004). Conclusions: While complete adjustment for all potential confounding factors was not possible, the findings suggest that patients who received loop diuretics within 48 hours had more severe kidney injury and a significantly higher mortality rate compared to those who received later administration (after 96 hours). These findings underscore the need for careful consideration when determining the timing of loop diuretic initiation in clinical practice.