Objective: Heart failure (HF) remains a global health burden, with anemia emerging as a critical comorbidity that worsens clinical outcomes. This study integrates hematological and histopathological analyses to unravel the interplay between anemia, iron deficiency, and cardiac tissue injury in 200 HF patients stratified by anemia status. Duration of Study: February 2023 to October 2024. Place of Study: Chaudhry Muhammad Akram Teaching and Research Hospital, Lahore ,Rashid Latif Medical College Lahore& Punjab Medical College, Faisalabad Medical University, Faisalabad, Pakistan. Methodology: A prospective cohort of 200 HF patients (NYHA II–IV) was stratified by WHO anemia criteria. Hemoglobin, serum ferritin, and NT-proBNP levels were analyzed alongside histopathological evaluation of right ventricular septal biopsies. Results: Anemic HF patients exhibited a 40% increase in fibrosis and 75% higher necrosis scores compared to non-anemic counterparts, driven by hypoxia and elevated ventricular stress (NT-proBNP). Multivariate regression confirmed hemoglobin (β = -0.45, *p* = 0.002), ferritin (β = -0.30, *p* = 0.01), and NT-proBNP (β = 0.50, *p* < 0.001) as independent predictors of fibrosis. Discussion: The observed cardiac injury in anemic HF patients is mechanistically linked to hypoxia-driven pathways, mitochondrial dysfunction, and ventricular strain. These findings underscore the synergistic role of anemia, iron deficiency, and neurohormonal activation in accelerating myocardial remodeling. Conclusion: These results advocate for anemia management as a therapeutic target to mitigate cardiac remodeling, emphasizing iron repletion and tailored interventions in high-risk HF populations.