Objective. To investigate the emotional response, stress and psychological changes of patients with breast cancer after surgery for psychological intervention-assisted comfort nursing based on the PERMA model. Methods. A total of 100 postoperative breast cancer patients admitted to our hospital from March 2019 to June 2021 were selected as prospective research objects. According to a random number table, they were divided into a control group and an observation group with 50 cases each. Among them, the control group implemented routine nursing care, and the observation group implemented psychological intervention-assisted comfort care based on the PERMA model on the basis of the control group. The differences in compliance behavior, self-care ability, emotional response, stress response changes, and pain scores of the two groups of breast cancer patients before and after nursing were compared. Results. After nursing, the mental behavior scores, exercise scores, medication scores, and balanced diet scores of the two groups of breast cancer patients after surgery were significantly improved. The observation group’s compliance behavior scores were significantly higher than those of the control group. In the two groups of breast cancer patients, postoperative anxiety, depression, fatigue, and anger of the patients were significantly improved, and the emotional response score of the observation group was significantly lower than that of the control group. The self-care skill score, self-responsibility score, health knowledge score, and self-concept score of the observation group were excellent compared with those of the control group; the difference was significant by the above statistics (
P
<
0.05
). The HR and MAP of the control group during the operation were higher than those 1 day before the start of the operation and decreased at the end of the operation, but still higher than the level 1 day before the start of the operation; the change trend of the observation group was the same as that of the control group, but there were differences between the time points. There was no significant significance (
P
>
0.05
). The HR and MAP of the observation group during the operation were lower than those of the control group, and the MAP at the end of the operation was lower than that of the control group. This difference was statistically significant (
P
<
0.05
). In the control group, the values increased at the time point during the operation and decreased at the end of the operation, but still higher than the level 1 day before the operation. The difference was statistically significant (
P
<
0.05
). The change trend of the observation group was the same as that of the control group; and the values during and at the end of the operation were all lower than those of the control group. This difference was statistically significant (
P
<
0.05
). The pain scores of the two groups of patients at different time points were significantly improved, and the observation group was significantly less than the control group. This difference was statistically significant (
P
<
0.05
). Conclusion. Psychological intervention-assisted comfort nursing can effectively enhance the compliance behavior of patients after breast cancer surgery, improve the emotional response, stress response, and pain of patients, and have certain reference value for the nursing of patients after breast cancer surgery.