Background: Chronic kidney disease (CKD) is one of the main public health issues. It increases the morbidity and mortality of patients. Treatment includes multiple aspects such as dialysis and lifestyle modifications. The primary goal of this study was to determine factors associated with self-efficacy and health-related quality of life (HRQoL) among haemodialysis (HD) patients. Methods: A cross-sectional descriptive correlation study was conducted on CKD patients undergoing HD at 12 different dialysis centres in Palestine. Self-efficacy was assessed by the Self-Efficacy for Managing Chronic Disease Six-Item Scale (SEMCD-6), and HRQoL was assessed using the Five-level EuroQol Five-Dimensions (EQ-5D-5L) tool. Multiple linear regression analysis was carried out to assess the association of factors with each of the SEMCD-6 and HRQoL scale scores. Results: A total of 283 HD patients were included in the study. A correlation test revealed moderately positive association between the EQ-5D and SEMCD-6 scores (r = 0.497, p value < 0.001). In multiple linear regression analysis, age, living status, and number of co-morbid diseases were negatively associated with SEMCD-6 scores (β = − 2.66, p = 0.016; β = − 5.71, p = 0.033; β = − 1.84, p = 0.006, respectively). Furthermore, there is a positive association between educational level and SEMCD-6 score with QoL score (β = 0.05, p = 0.017; β = 0.01, p < 0.001, respectively), while there is a negative association between the number of co-morbid diseases and QoL score (β = − 0.07, p = 0.001).Conclusions: This study assessed factors associated with impaired self-efficacy and HRQoL in HD patients. The results show that impaired self-efficacy was associated with the elderly, patients living with family, and patients with a high number of co-morbid diseases. Furthermore, this study found that the worst HRQoL was associated with patients with a low education level, lower levels of self-efficacy, and a high number of co-morbid diseases.