Coronary artery bypass grafting (CABG) surgery with two methods (on‐pump or off‐pump) can be used to rescue individuals with severe coronary artery disease (CAD). Each method might cause an inflammatory response, which can lead to some complications. The aim of this study was to compare the changes in serum concentrations of IFN‐γ, tumor necrosis factor (TNF)‐α, interleukin (IL)‐1α, IL‐1β, IL‐2, IL‐4, IL‐6, IL‐8, IL‐10, VEGF, MCP‐1, and epidermal growth factor between the two CABG surgery methods. Forty‐eight patients (22 = on‐pump, 26 = off‐pump) who underwent on‐pump or off‐pump CABG surgery were enrolled in this study. Serum cytokines levels were measured in two blood samples, the first sample was taken from each patient in the morning of the day of surgery after a 12‐hr fasting and the second sample on the first postoperative day at 24‐hr after surgery. In baseline, comparisons between the two groups of on‐pump/off‐pump surgery did not show any significant difference in demographic data, anthropometric parameters, lipid profile indices, and high‐sensitivity C‐reactive protein levels (p > .05). There was a significant difference between the serum levels of IL‐4, IL‐6, IL‐10, vascular endothelial growth factor (VEGF), IFN‐γ, and MCP‐1 in patients with on‐pump surgery and a significant increase in serum IL‐6 (p < .001), IL8 (p < .05), VEGF (p < .001), and IFN‐γ (p < .01) levels in patients with off‐pump surgery in post‐operation stage compared to pre‐operation. Cardiopulmonary pump in patients under CABG surgery can activate systemic inflammation and the changes of serum cytokines levels in off‐pump CABG were lower compared with on‐pump CABG.