ObjectiveTo systematically evaluate the association between fluid balance at different time points and mortality in patients with septic shock, and to provide evidence-based guidance for optimal timing of fluid management in clinical practice. MethodsWe electronically searched CNKI, WanFang Data, VIP, CBM, PubMed, Embase, Web of Science, and Cochrane Library databases from inception to December 2024 for original studies investigating the relationship between fluid balance and mortality in patients with septic shock. Two reviewers independently screened literature, extracted data, and assessed risk of bias. Meta-analyses were performed using Stata 16.0 and RevMan 5.4 software. ResultsA total of 16 original studies involving 36 573 patients with sepsis or septic shock were included. Meta-analysis showed that 24 hours fluid balance was not significantly associated with mortality (OR=0.92, 95%CI 0.71 to 1.19, P=0.52), suggesting a potential protective effect of early moderate positive fluid balance; 48 hours cumulative positive fluid balance was significantly associated with increased mortality (OR=1.52, 95%CI 1.28 to 1.81, P<0.001); this association strengthened further at 72 hours (RR=1.65, 95%CI 1.38 to 1.98, P<0.001); and a fluid accumulation index >0.42 was also significantly linked to higher in-hospital mortality (OR=1.46, 95%CI 1.10 to 1.95, P<0.05). Subgroup analyses based on 72 hours fluid balance demonstrated consistent results across study designs, geographic regions, sample sizes, sepsis diagnostic criteria, and adjustment for confounders. Sensitivity analyses and publication bias assessments confirmed the robustness of the findings. ConclusionThe impact of fluid balance on mortality in septic shock exhibits clear time dependency: moderate positive fluid balance within the first 24 hours may be beneficial, but sustained positive balance beyond 48 hours is significantly associated with increased mortality, with 72 hours representing a critical window. It is recommended to transition to a restrictive fluid strategy within 48–72 hours after initial resuscitation, and to initiate fluid de-resuscitation in patients without fluid responsiveness to improve outcomes.