Background: The majority of patients living with chronic pain faces several challenges; therefore, factors affecting their adaptation to the disease to provide appropriate therapeutic methods and meditation and relaxation therapy should be identified. Objectives: The present study aimed at investigating the relationship between perceived burdensomeness and psychosocial adjustment, and the mediating role of pain self-efficacy. Methods: This descriptive correlational study was conducted on 240 patients with chronic pain referred to the orthopedic centers in Ardabil in 2019 selected by convenience sampling. Psychosocial Adjustment to Illness Scale, Pain Self-efficacy Questionnaire, and Interpersonal Needs Questionnaire were used for data collection. Also, Pearson correlation and multiple regressions were used for data analysis. Data were analyzed using SPSS V. 19 and AMOS V. 21. Results: The findings confirmed the negative and direct effect of perceived burdensomeness (β = -0.11 and P < 0.01), as well as the positive and direct effect of pain self-efficacy (β = 0.86 and P < 0.01) on psychosocial adjustment. On the other hand, perceived burdensomeness (β = -0.32, P < 0.01) had a negative and direct effect on pain self-efficacy. The indirect effect of perceived burdensomeness and pain self-efficacy on psychosocial adjustment to illness was also confirmed. Conclusions: According to the findings of the present study, it can be concluded that the feelings of pain self-efficacy mediate the relationship between perceived burdensomeness and psychosocial adjustment in patients with chronic pain. That can also be important for the patient and their caregivers in relation to other chronic illnesses. Chronic diseases can also affect patients and their caregivers.