Fluid overload is associated with acute kidney injury (AKI) and mortality. There is no convenient precise method to guide fluid therapy in critically ill patients. We aimed to investigate whether brain natriuretic peptide (BNP) can predict the renal outcome and mortality of critically ill patients and be used to guide fluid management. Methods: This prospective observational study included patients who were admitted to the intensive care unit (ICU). Patients with underlying heart disease and heart dysfunction were excluded. Plasma BNP levels were obtained on admission (D0), at 24 hours (D1), and at 48 hours (D2). The primary outcome was AKI development during the ICU stay and recovery of AKI at ICU discharge. The secondary outcome was in-ICU mortality. Results: One hundred and sixty-three patients were enrolled for analysis. The delta-BNP level within the initial 24 hours after ICU admission rather than fluid accumulation was significantly correlated with delta-central venous pressure levels (r = 0.219, p = 0.010). Delta-Brain natriuretic peptide levels of < 81.8% within the initial 24 hours was an independent predictor of better renal outcome (i.e., no AKI or AKI with recovery). The increment in the BNP level from D0 to D1 was also a significant risk factor of mortality. In the a priori subgroup analysis for patients with sepsis, delta-BNP levels from D0 to D1 remained a significant predictor of renal outcome and mortality. Conclusion: Our study showed that delta-BNP levels within 24 hours of admission to the ICU are better than fluid accumulation as a predictor of AKI, recovery, and mortality.