Objective This study observed the effect of lidocaine combined with dexmedetomidine on inflammatory factors in patients with gastric cancer undergoing intraperitoneal hyperthermic perfusion chemotherapy. Methods Eighty patients who received hyperthermic intraperitoneal chemotherapy (HIPEC) under general anesthesia for radical gastrectomy (Transabdominal total gastrectomy+Roux‑en‑Y anastomosis of esophagus and jejunum). The patients were randomly assigned into control group (group C), dexmedetomidine group (group D), lidocaine group (group L) and dexmedetomidine combined lidocaine group (group DL) (n=20). Intravenous pumping of the corresponding drugs 10 min before the induction of anesthesia, followed by continuous infusion until 30 min before the end of the perfusion. Peripheral venous blood was collected from patients before induction of anesthesia (T1), at the end of surgery (T2), at the end of perfusion (T3), 2 h (T4) and 24 h (T5) after surgery. The levels of serum interleukin (IL)‑6 and tumor necrosis factor‑α (TNF‑α) at T1, T2, T3, T4 and T5 in each group were measured. The serum IL‑6 and TNF‑α levels, recovery and extubation time, remifentanil and propofol consumption of patients in each group at T1, T2, T3, T4 and T5 were recorded and analyzed. Results Compared with group C, serum levels of TNF‑α were significantly reduced in group L at T4 and T5 (P<0.05), serum levels of IL‑6 and TNF‑α were significantly reduced in group D and group DL at T2‒T5 (P<0.05). Compared with group L, serum levels of IL‑6 and TNF‑α were significantly reduced in group D and group DL at T2‒T5 (P<0.05). Compared with group D, serum levels of IL‑6 and TNF‑α decreased in group DL at T2‒T5 (P<0.05). Compared with group C, the time required for recovery and extubation, and the dosage of remifentanil and propofol were not statistically different in group L (P>0.05), the time required for recovery and extubation was longer in group D and group DL, and the dosage of remifentanil and propofol was smaller (P<0.05). Compared with group L, the recovery and extubation time was longer in group D and group DL, and the dosage of remifentanil and propofol was smaller (P<0.05). The time required for recovery and extubation in group DL was significantly longer than that in group D, and the dosage of remifentanil and propofol was significantly less than that in group D (P<0.05). Conclusions Intravenous infusion of dexmedetomidine combined with lidocaine can reduce the inflammatory response caused by radical gastrectomy combined with HIPEC.