The prognostic factors and pharmacological effects of the very elderly patients (aged ≥80 years) with acute heart failure (AHF) remain unclear. The study, therefore, investigated the prognostic impacts of the guideline-recommended pharmacological therapy in these patients. A cohort of 1297 very elderly patients [85.1 ± 4.0 years, 69.7% male, 32.6% heart failure with reduced left ventricular ejection fraction (LVEF), HFrEF], hospitalized for AHF, was studied. The percentage of the recommended prescription for HFrEF at discharge, including renin-angiotensin system inhibitors, β-blockers, and mineralocorticoid receptor antagonists, was calculated as guideline adherence indicator (GAI). Among the 1233 survivors at discharge, 495 subjects (40.1%) died during a mean follow-up of 27.1 ± 23.9 months. Mean GAIs in HFrEF and HFpEF were 70.6 ± 34.9% and 64.1 ± 35.9%, respectively. A higher GAI was associated with less overall mortality [hazard ratio and 95% confidence interval per-1SD: 0.781, 0.655-0.930] and cardiovascular death (0.718, 0.558-0.925), independent of age, gender, diabetes, hypertension, mean blood pressure, LVEF, eGFR, sodium, and NT-proBNP. A GAI of 100% was associated with a better survival in both HFrEF and HFpEF. A prescription of the three recommended medications for HFrEF to the very elderly AHF patients was associated with a better survival after discharge.