Cardiogenic shock (CS) portends a dismal prognosis if hypoperfusion triggers uncontrolled inflammatory and metabolic derangements. We sought to investigate metabolomic profiles and temporal changes in IL6, Ang-2, and markers of glycocalyx perturbation from admission to discharge in eighteen patients with heart failure complicated by CS (HF-CS). Biological samples were collected from 18 consecutive HF-CS patients at admission (T0), 48 h after admission (T1), and at discharge (T2). ELISA analytical techniques and targeted metabolomics were performed Seven patients (44%) died at in-hospital follow-up. Among the survivors, IL-6 and kynurenine were significantly reduced at discharge compared to baseline. Conversely, the amino acids arginine, threonine, glycine, lysine, and asparagine; the biogenic amine putrescine; multiple sphingolipids; and glycerophospholipids were significantly increased. Patients with HF-CS have a metabolomic fingerprint that might allow for tailored treatment strategies for the patients' recovery or stabilization.