Chronic heart failure (CHF) is frequently complicated by chronic kidney disease (CKD), a comorbidity that profoundly influences disease progression, therapeutic decision-making, and clinical outcomes. The management of CHF in patients with advanced CKD presents substantial challenges, often requiring dose adjustments or even discontinuation of standard therapies. Effective therapeutic strategies must prioritize cardiorenal protection during the early stages of disease progression. Recent advancements in pharmacotherapy, including angiotensin receptor-neprilysin inhibitors, sodium-glucose cotransporter 2 inhibitors, non-steroidal mineralocorticoid receptor antagonists, and glucagon-like peptide-1 receptor agonists, have demonstrated remarkable dual cardiorenal protective effects. These therapies not only reduce the risk of de novo heart failure in high-risk populations and improve clinical outcomes in CHF patients, but also slow the progression of renal dysfunction by targeting critical pathophysiological processes, such as glomerular hyperfiltration, inflammation, ischemia, and endothelial dysfunction. Although transient declines in estimated glomerular filtration rate may occur upon initiating these agents, renal function typically stabilizes over time, facilitating sustained clinical benefits, particularly in patients with diabetes mellitus, albuminuric CKD, and CHF. This review focuses on the latest advancements in heart failure pharmacotherapy, emphasizing the cardiorenal protective mechanisms and clinical efficacy of novel therapeutic agents. It underscores the importance of bridging knowledge gaps and personalizing therapy to enhance cardiorenal benefits avoiding adverse effects.