Aims Insulin‐like growth factor binding protein‐7 (IGFBP7) is a biomarker of tissue senescence with a role in cardio‐renal pathophysiology. The role of IGFBP7 as a prognostic biomarker across the full ejection fraction (EF) spectrum of heart failure (HF) remains less well understood. We examined associations between IGFBP7 and risk of cardio‐renal outcomes regardless of EF and the effect of empagliflozin treatment on IGFBP7 concentrations among individuals with HF. Methods and results IGFBP7 was measured in 1125 study participants from the EMPEROR‐Reduced and EMPEROR‐Preserved trials. Cox regression was used to study associations with outcomes. Study participants with IGFBP7 levels in the highest tertile had a higher‐risk clinical profile. In Cox proportional hazards models adjusted for clinical variables, N‐terminal pro‐B‐type natriuretic peptide and high‐sensitivity cardiac troponin T, baseline IGFBP7 values in the highest tertile predicted an increased risk of HF hospitalization or cardiovascular death (hazard ratio [HR] 2.00, 95% confidence interval [CI] 1.28–3.10, p = 0.002, p for trend <0.001) and higher risk of the renal composite endpoint (HR 4.66, 95% CI 1.61–13.53, p = 0.005, p for trend = 0.001), regardless of EF. Empagliflozin reduced risk for cardiovascular death/HF hospitalization irrespective of baseline IGFBP7 ( p for trend across IGFBP7 tertiles = 0.26). Empagliflozin treatment was not associated with meaningful change in IGFBP7 at 12 or 52 weeks. Conclusion Across the entire left ventricular EF spectrum in the EMPEROR Programme, concentrations of the senescence‐associated biomarker IGFBP7 were associated with higher risk clinical status and predicted adverse cardio‐renal outcomes even in models adjusted for conventional biomarkers. Empagliflozin did not significantly affect IGFBP7 levels over time.