Objective  To explore the relationship between blood pressure variability during dialysis and post-dialysis fatigue in maintenance hemodialysis (MHD) patients.  Method  Patients undergoing MHD at the Blood Purification Center of Renji Hospital affiliated to Shanghai Jiao Tong University School of Medicine from November 2024 to February 2025 were enrolled in this study. Blood pressure was measured for a total of 6 times in a hemodialysis session, and the coefficient of variation (CV) of blood pressure was calculated. The Visual Analog Fatigue Scale was used to evaluate post-dialysis fatigue symptoms. The relationship between CV of blood pressure during dialysis and post-dialysis fatigue was analyzed. Patients were divided into four groups based on the quartiles of CV of blood pressure. Comparisons were made among the groups.  Result  A total of 285 patients were included, with a post-dialysis fatigue score of 4.00 (3.00, 6.00). Correlation analysis showed that the CV of systolic blood pressure, diastolic blood pressure, and pulse pressure were positively correlated with post-dialysis fatigue (r=0.243, 0.108 and 0.119 respectively; P<0.001, 0.034 and 0.023 respectively). Intergroup comparisons showed that post-dialysis fatigue increased along with the groups of increased systolic blood pressure variation (for systolic blood pressure variation: low variation group 71 cases, medium-low variation group 72 cases, medium-high variation group 71 cases, and high variation group 71 cases; χ²=17.184, P=0.001); post-dialysis fatigue initially decreased and then increased along with the groups of increased diastolic blood pressure variation (for diastolic blood pressure variation: low group variation 71 cases, medium-low variation group 72 cases, medium-high variation group 71 cases, and high variation group 71 cases; χ²=11.988, P=0.007); post-dialysis fatigue had no correlation with pulse blood pressure variation among the groups (for pulse blood pressure variation: low variation group 71 cases, medium-low variation group 72 cases, medium-high variation group 71 cases, and high variation group 71 cases; χ²=3.048, P=0.284). Post-dialysis fatigue was predominantly affected by the CV of systolic blood pressure (χ2=17.208, P=0.001) in elderly MHD patients (n=177), and by the CV of diastolic blood pressure (χ2=11.275, P=0.010) in non-elderly MHD patients (n=108).  Conclusion Blood pressure variation during dialysis is associated with post-dialysis fatigue. The key point to manage post-dialysis fatigue is different between elderly and non-elderly MHD patients: control of systolic blood pressure variation is suitable for elderly MHD patients, whereas reduction of diastolic blood pressure variation is warranted for non-elderly MHD patients.