Patients with acute decompensated heart failure (ADHF) frequently develop worsening in renal function until Acute Kidney Injury (AKI). The use of kidney injury biomarkers could be useful in the early diagnosis of AKI. In the present study, the role of the neutrophil gelatinase-associated lipocalin (NGAL), compared to the standard creatinine, in ADHF patients, was analyzed to evaluate if an early treatment could affect the outcome. A case series of 24 ADHF patients was enrolled and patients randomly divided in two groups (Group A and Group B). In Group A, NGAL, creatinine, and eGFR were measured, while in Group B, creatinine and eGFR alone were measured. NGAL was measured by turbidimetric immunoassay and creatinine using an enzymatic spectrophotometric method. In presence of AKI, creatinine increase and eGFR decrease were significantly lower in Group A than in Group B, whereas in absence of AKI the difference between the two groups was not significant. Hospitalization stay was significantly lower in Group A (receiving early treatment based on NGAL) than in Group B. In ADHF patients, plasma NGAL in combination with creatinine was superior to the standard creatinine in the diagnosis and early treatment of AKI with a better outcome and a decreased hospital stay.