Spirituality-centered cognitive therapy refers to the way in which people search for and express the meaning and purpose of their lives, as well as experience connection with themselves, others, nature, and spirituality. This study aimed to determine the effectiveness of spirituality-centered cognitive therapy on body image, sexual function, disease perception, and disturbing thoughts in women after mastectomy. This was semi-experimental research, which was conducted via a pre-test–post-test method and had a control group. The samples included 85 women with breast cancer who had undergone mastectomy, and, based on the inclusion criteria, 78 individuals were randomly selected and were then divided into two groups (39 individuals in the intervention group and 39 individuals in the control group). The intervention group received eight 120 min sessions of spirituality-centered cognitive therapy, and the control group did not receive any training. Data were collected using questionnaires on illness perception, body image, sexual function, and rumination and were then analyzed by multivariate analysis of variance with repeated measurements using SPSS-24. Before the training, there was no significant difference between the intervention and control groups in the scores obtained by the scales. After the intervention, the mean scores in all scales except sexual function were significantly different from the control group. Therefore, spirituality-centered cognitive therapy may be useful for improving negative psychological symptoms among women in Iran with breast cancer after mastectomy surgery.