Background: The combination of surgery, bacterial spread-out, and artificial cardiopulmonary bypass surfaces results in a release of key inflammatory mediators leading to an overshooting systemic hyper-inflammatory condition frequently associated with compromised hemodynamics and organ dysfunction. A promising approach could be extracorporeal blood purification therapies in combination with IgM enriched immunoglobulin. This approach might perform a balanced control of both hyper and hypo-inflammatory phases as an immune-modulating intervention. Methods: We performed a retrospective observational study of patients with proven infection after cardiac surgery between January 2020 and December 2021. Patients were divided into two groups: (1) the first group (Control Group) followed a standard care approach as recommended by the Surviving Sepsis Campaign Guidelines; The second group (Active Group) underwent extracorporeal blood purification therapy (EBPT) in combination with intravenous administration of IgM enriched immunoglobulin 5 mL/kg die for at least three consecutive days, in conjunction with the standard approach (SSC Guidelines). In addition, ventriculo-arterial (V/A) coupling, Interleukin 6 (IL-6), Endotoxin Activity Assay (EAA), Procalcitonin, White Blood Cells (WBC) counts, Sequential Organ Failure Assessment (SOFA) Score and Inotropic Score were assessed in both two groups at different time points. Results: Fifty-four patients were recruited; 25 were in the Control Group, while 29 participants were in the Active Group. SOFA score significantly improved from baseline [12 (9–16)] until at T{}_3 [8 (3–13)] in the active group; it was associated with a median EAA reduction from 1.03 (0.39–1.20) at T{}_0 to 0.41 (0.2–0.9) at T{}_3 in the active group compared with control group 0.70 (0.50–1.00) at T{}_0 to 0.70 (0.50–1.00) at T{}_3 (p 0.001). V/A coupling tended to be lower in patients of the active arm ranging from 1.9 (1.2–2.7) at T{}_0 to 0.8 (0.8–2.2) at T{}_3 than in those of the control arm ranging from 2.1 (1.4–2.2) at T0 to 1.75 (1.45–2.1) at T{}_3 (p = 0.099). The hemodynamic improvement over time was associated with evident but no significant decrease in inotropic score in the active group compared with the control group. Changes in EAA value from T{}_0 to T{}_4 were directly and significantly related (r = 0.39, p = 0.006) to those of V/A coupling. Conclusions: EBPT, in combination with IgM enriched immunoglobulin, was associated with a mitigated postoperative response of key cytokines with a significant decrease in IL-6, Procalcitonin, and EAA and was associated with improvement of clinical and metabolic parameters.