This review summarizes the two-way interactions between the gut microbiota and key HF drugs, including digoxin, angiotensin receptor-neprilysin inhibitors (ARNIs), ACE inhibitors (ACEIs), angiotensin receptor blockers (ARBs), β-blockers, sodium-glucose cotransporter 2 (SGLT2) inhibitors, mineralocorticoid receptor antagonists (MRAs), and diuretics. This evidence concerns the gene ACE and hydrops fetalis.