Objective: To explore the effect of different approaches of laparoscopic cholecystectomy on inflammation and stress indexes in patients with acute cholecystitis and gallstones, and to provide reference for clinical treatment of the disease. Methods: This study is a retrospective study. A total of 104 patients with acute cholecystitis and gallstones were selected from Changge Hospital of Traditional Chinese Medicine. The cases were completed from January 2021 to April 2025. They were divided into the group A (51 cases, antegrade/retrograde stripping laparoscopic cholecystectomy ), the group B (53 cases, lateral approach stripping laparoscopic cholecystectomy). Both groups were observed until discharge. The perioperative indexes, pain visual analogue scale (VAS) at before and 12,24 and 48 h after operation, inflammation and stress indexes before and 3 d after operation, and complications during observation were compared and analyzed between the two groups. Results: The amount of bleeding in the group A and the group B was compared, and the group B was less; compared with hospitalization time and drainage tube indwelling time, group B was shorter ; compared with before operation, the VAS scores of the group A and the group B at 12 h~48 h after operation showed a trend of increasing first and then decreasing, and the group B was lower. The levels of serum C-reactive protein (CRP), interleukin-1β (IL-1β), adrenocortical hormone (ACTH) and cortisol (Cor) in the group A and group B were higher than those before operation, but those in group B were lower than those in the group A at 3 days after operation. The total incidence of complications during the observation period of the group A and the group B was compared, and the group B was lower. (P<0.05). Conclusion: For patients with acute cholecystitis and gallstones, the use of lateral approach stripping laparoscopic cholecystectomy can significantly optimize the surgical outcome, which is manifested in the effective reduction of intraoperative blood loss, while shortening the length of hospitalization and the indwelling time of drainage tube, reducing the degree of postoperative pain, and alleviating the effect of surgery on inflammation and stress response, reducing the risk of complications.