To explore the effect of the stress response and comfort of the perioperative path nursing for patients with myomectomy. Methods: 100 patients after myomectomy were selected and were divided into the control group and the observation group (50 cases in each group) according to the random number table method from January 2021 to February 2023. The patients in the two groups were given routine nursing, and the patients in the observation group were given perioperative path nursing additionally. The postoperative related indicators levels, the values of perioperative stress response (blood pressure, heart rate and respiration), the pain degree on the first day after operation, the scores by Kolcaba Comfort questionnaire (GCQ), self-rating anxiety scale (SAS) and selfrating depression scale (SDS) before and after nursing intervention, and the complications rate of the patients were compared between the two groups. Results: The first ventilation time (0.89±0.19d), the time of the first time of getting out of bed (7.21±1.06h) and the hospital stay (3.12±1.03d) of the patients in the observation group were significantly lower than those (1.01±0.25d, 8.05±1.32h and 4.06±1.12d) of the patients in the control group. The values of intraoperative blood pressure, heart rate and respiration of the patients in the two groups had increased to varying degrees, and the values of postoperative blood pressure, heart rate and respiration of the patients in the two groups had decreased to varying degrees, and all of which of the patients in the observation group were significantly lower than those of the patients in the control group (P<0.05). The degree of pain of the patients in the observation group was significantly lower than that of the patients in the control group. The scores of SAS and SDS of the patients in the two groups had decreased significantly, and the GCQ score of the patients in the two groups had increased significantly, and the changes of which in the observation group were significantly greater than those of the patients in the control group. The total complication rate (8.0%) of the patients in the observation group was significantly lower than that (28.0%) of the patients in the control group (all P<0.05). Conclusion: The perioperative path nursing for the patients with myomectomy can effectively improve their stress response and psychological state, enhance their postoperative comfort and reduce their incidence of complications, and which contributes to their postoperative recovery.