Objective To evaluate the clinical value of laparoscopic cholecystectomy versus open cholecystectomy in improving postoperative inflammatory response, stress state, and prognosis in middle-aged and elderly patients with cholelithiasis and cholecystitis, and to provide a reference basis for the selection of clinical cholecystectomy procedures. Methods A retrospective controlled study method was used to include 120 middle-aged and elderly patients with calculous cholecystitis admitted to the Department of Hepatobiliary, Pancreatic, and Hernia Surgery of Fujian Provincial Geriatric Hospital from January 2022 to June 2024, who were divided into laparoscopic and open groups according to the surgical methods (n=60). Surgery-related indicators (operative time, intraoperative blood loss, postoperative recovery time, length of hospital stay, etc.) were compared between the two groups; serum inflammatory factor levels [Interleukin-6 (IL-6), Tumor Necrosis Factor-alpha (TNF-α), C-Reactive Protein (CRP)] were detected preoperatively and at different postoperative time points (6h, 24h, 72h); stress hormone levels (cortisol, epinephrine, norepinephrine) were measured preoperatively and at 6h and 24h postoperatively; complications occurring within 30 days postoperatively were recorded. Results The laparoscopic group was significantly superior to the open group in all surgery-related indicators (All P<0.05): shorter operative time [(62.3±12.8) min vs. (78.6±15.2) min], less intraoperative blood loss [(58.4±8.6) mL vs. (116.3±28.7) mL], earlier first flatus time [(22.2±4.3) h vs. (31.6±7.8) h] and first feeding time [(16.8±3.2) h vs. (24.5±5.6) h], shorter hospital stay [(5.8±1.1) days vs. (7.8±2.3) days], and smaller incision length [(1.5±0.3) cm vs. (10.8±2.1) cm]. At all postoperative time points, the levels of IL-6, TNF-α, and CRP in the laparoscopic group were significantly lower than those in the open group (All P<0.05). At 6h and 24h postoperatively, the levels of cortisol, epinephrine, and norepinephrine in the laparoscopic group were significantly lower than those in the open group (All P<0.05). The total complication rate in the laparoscopic group was significantly lower than that in the open group (8.3% vs. 46.7%, P<0.05). Conclusion Compared with open cholecystectomy, laparoscopic cholecystectomy has the advantages of minimal trauma and rapid recovery, and can significantly reduce postoperative inflammatory response and stress response, decrease the incidence of complications, and improve prognosis in middleaged and elderly patients with cholelithiasis and cholecystitis, providing patients with safe and effective treatment options.