<p>Cluster of differentiation 38 (CD38) is a widely expressed transmembrane glycoprotein in various human tissues and cells with vital biological roles in the heart and brain, possessing both NADase and cyclase activities. It is involved in regulating heart and brain functions through various pathways, including calcium (Ca²⁺) signaling nicotinamide adenine dinucleotide (NAD⁺) content, oxidative stress, inflammation and immune response. Its combined role in heart-brain coexisting diseases suggests that inhibiting CD38 has a protective effect on cardiovascular diseases (CVD) and neurological disorders. This review aims to discuss the expression patterns, regulatory mechanisms, and CD38 signaling pathways in the heart and brain. In conclusion, CD38 is implicated in the shared pathogenesis of heart-brain diseases, providing novel insights for future research.</p>