Background <p>Myocardial infarction (MI) is among the leading causes of death worldwide, and a precisely regulated inflammatory response is essential for effective cardiac repair and long-term outcome. The serotonergic system regulates immune cell functions, yet its contribution to post-MI remodeling is incompletely understood.</p> Methods <p>Here, we investigated the role of serotonin receptor 7 (5-HT7R) in post-infarction inflammation and outcome after permanent left anterior coronary artery ligation in mice, and complementary analysis of peripheral blood mononuclear cells (PBMCs) obtained from patients with acute MI.</p> Results <p>Three days after MI, 5-HT7R mRNA expression was significantly upregulated in the infarct region compared to remote myocardium and sham operated mice. RNA-sequencing of isolated murine CD11b⁺ cells demonstrated high 5-HT7R expression in cardiac macrophages during the acute phase, which was confirmed by immunohistochemistry. Systemic 5-HT7R-knockout did not affect basal cardiac function but resulted in impaired left ventricular function and enhanced inflammatory signatures 14 days after MI without changes in infarct size. Pharmacological activation of 5-HT7R signaling with the selective agonist LP-211 increased survival after MI, although global systolic function among survivors was not improved. Transcriptomic profiling of cardiac macrophages 3 days after MI revealed bidirectional regulation of inflammatory and metabolic programs depending on 5-HT7R activity, including altered expression of <i>Got1</i> and <i>S100A9</i>. Complementary, in PBMCs from MI patients <i>Got1</i> expression was reduced, while <i>S100A9</i> was increased, and both correlated with 5-HT7R expression.</p> Conclusions <p>These data suggest 5-HT7R as a regulator of post-MI immune responses and a potential target to improve repair and survival.</p>