Objective To compare the effects of laparoscopic and open radical gastrectomy on inflammatory response, immune function and pain mediators in patients with advanced gastric cancer. Methods The 86 patients with advanced gastric cancer in our hospital from June 2019 to June 2020 were selected and divided into laparoscopic group (n = 43) and open group (n = 43) according to different surgical methods. The laparoscopic group was treated with laparoscopic surgery, while the open group was treated with open surgery. Then we compared the surgery-related indicators and complications, and the changes in inflammatory response [C-reactive protein (CRP) and interleukin-6 (IL-6)], immune function [CD3+ cell count, CD4+ cell count and CD4+/CD8+ ratio] and pain mediators [5-hydroxytryptamine (5-HT), substance P (SP) and norepinephrine (NE)] before and 3 days after the surgery between the two groups. Results The intraoperative blood loss in the open group was more than that in the laparoscopic group (P < 0.05). The recovery time of gastrointestinal tract and the operation time in open group were both longer than those in laparoscopic group (P < 0.05). The incidence of postoperative complications in open group was higher than that in laparoscopic group (P < 0.05). The differences of serum CRP and IL-6 before and after operation were higher in open group (P < 0.05); the differences of CD3+ cell count, CD4+ cell count and CD4+/CD8+ ratio before and after operation were greater in laparoscopic group (P < 0.05); while the differences of serum 5-HT, SP and NE before and after operation were higher in open group (P < 0.05). Conclusion Laparoscopic radical gastrectomy for advanced gastric cancer contributes to fewer postoperative complications and faster recovery of gastrointestinal function, and has less impact on inflammatory response, immune function and pain mediators.