Abstract: Objective To investigate the effect of esketamine combined with general anesthesia and transversus abdominis plane block (TAPB) in obese patients undergoing laparoscopic surgery. Methods A total of 100 obese patients scheduled for laparoscopic surgery at Huaibei People's Hospital from January 2023 to February 2025 were assigned, using a random number table, to either an intervention group (esketamine combined with general anesthesia and TAPB) or a control group (general anesthesia combined with TAPB), with 50 cases in each. The hemodynamics, recovery quality, postoperative dynamic and static Visual Analogue Scale (VAS) pain scores, and the analgesic rescue rate within 24 hours, the 40-item Quality of Recovery Scale (QoR-40) at 24 hours postoperatively, stress response indicators, and adverse reactions were compared between the two groups. Results Compared with the control group, the systolic and diastolic blood pressures of the intervention group after pneumoperitoneum establishment and skin incision were lower, and the heart rate was slower (P ＜ 0.05), but the values of both groups were increased compared to before anesthesia induction levels (P ＜ 0.05). The intervention group also demonstrated earlier recovery of spontaneous breathing, earlier time to awakening and extubation, lower postoperative dynamic and static VAS scores, a lower 24-hour analgesic rescue rate, and higher QoR-40 scores at 24 hours postoperatively (P ＜ 0.05). Stress response indicators at 24 hours postoperatively were lower in the intervention group than in the control group (P ＜ 0.05), though they remained elevated above preoperative values in both groups (P ＜ 0.05). There was no statistically significant difference in the incidence of adverse reactions between the two groups (P ＞ 0.05). Conclusion For obese patients undergoing laparoscopic surgery, the combination of esketamine with general anesthesia and TAPB can stabilize intraoperative hemodynamics, alleviate postoperative pain, enhance recovery quality, attenuate the surgical stress response, and demonstrate a favorable safety profile.