The aim of this study was to investigate the association between serum albumin to serum creatinine ratio (sACR) and the prognosis of heart failure (HF). In this single-center prospective cohort study, a total of 2625 patients with HF were enrolled between March 2012 and June 2017. All patients were divided into three groups according to the tertiles of sACR. Of 2625 patients, the mean age was 57.0 ± 14.3 years. During a median follow-up time of 23 months, 666 end point events occurred. Prognosis analysis indicated that the lowest sACR was significantly associated with higher mortality risk of HF (hazard ratio [HR] = 1.920, 95% confidence interval [CI] = 1.585-2.326, p < 0.001) when compared with the highest tertile. After adjusting for covariates including age, gender, diabetes, systolic blood pressure (SBP), diastolic blood pressure, heart rate, total cholesterol, triglycerides, HDL-C, LDL-C, white blood cell count, hemoglobin, glycosylated hemoglobin, and β-blocker use, the HRs for mortality risk of HF was 1.513 (95% CI = 1.070-2.139, p = 0.019). Subgroup analysis indicated that the mortality risk of HF statistically significantly reduced with the rise in sACR in patients with no β-blocker use, patients with serum creatine less than 97 μmol/L. However, stratification by age, sex, history of hypertension, diabetes, and smoking, level of glycosylated hemoglobin, and albumin have no obvious effect on the association between sACR and the prognosis of HF. Additionally, patients with lower sACR displayed reduced left ventricular ejection fraction and increased left ventricular end-diastolic diameter. The discriminant power of sACR alone and in combination with age, gender, SBP, heart rate, and glycosylated hemoglobin were excellent with C statistic of 0.655 and 0.889, respectively. Lower sACR was an independent risk factor for mortality risk of HF.