Background Migraine is a neurological disease that has several physical and psychological complications, which is characterized by disability and impaired quality of life. Aims The aim of this study was to explore the mediating role of pain self-efficacy in the relationship between meaning of life, perceived social support, spiritual well-being and pain catastrophizing with quality of life in migraine sufferers. The relationship between these factors with quality of life (QOL) was not fully explored in migraine patients. Method This study was a correlational study of structural equations. Therefore, 300 patients with migraine who referred to one of the specialized neurological treatment centers in Zanjan in 2021 were recruited based on the inclusion criteria. Patients also completed the World Health Organization Quality of Life Scale (WHOQOL-BREF), Meaning in Life Questionnaire, Multidimensional Scale of Perceived Social Support, Spiritual Well-Being Scale, Pain Catastrophizing Scale, Pain Self-Efficacy Questionnaire. Finally, the hypotheses were then analyzed with correlation coefficient and path analysis method by using SPSS-26 and LISREL-10.2 programs. Results The results of the present study showed that pain self-efficacy has a mediating role in the relationship between meaning of life and quality of life (B = 0.015), perceived social support with quality of life (B = 0.022), spiritual well-being with quality of life (B = 0.021), as well as pain catastrophizing with quality of life (B = − 0.015). Conclusion According to the results of this study, by considering the role of self-efficacy of pain, it is possible to develop the programs to strengthen and improve the meaning of life, perceived social support, spiritual well-being and also reduce pain catastrophizing, in order to improve the quality of life of patients with migraine.