Cardiopulmonary bypass (CPB) contributes to the secretion of anti-inflammatory cytokines that mediate the inflammatory response observed during open heart surgery. In addition to many factors, type of anesthesia management affects immune response and central nervous system in cardiac surgery. The aim of this study was to assess the effect of propofol versus desflurane anesthesia on systemic immune modulation and central nervous system on patients undergoing coronary artery bypass grafting. Forty patients undergoing elective coronary artery bypass graft surgery with CPB were included in this prospective randomized study. Patients were allocated to receive propofol (n = 20) or desflurane (n = 20) for maintenance of anesthesia. The blood samples for IL-6, IL-8, TNF-α, and S100β were drawn just prior to the operation before the induction of anesthesia, second before cardiopulmonary bypass, third after CPB, fourth 4 h postoperatively at the ICU. Major finding in our study is that S100β levels were lower in propofol group when compared to desflurane anesthesia. And also immune reaction was less in patients exposed to desflurane anesthesia when compared to propofol anesthesia as indicated by lower plasma concentrations of IL-8 and IL-6. Propofol is more preferable in terms of S100β for anesthetic management for CABG.