Background: Postdialysis fatigue (PDF) is not an unusual symptom among hemodialysis (HD) patients; however, its causes remain unclear. The aim of this study was to analyze the factors responsible for PDF in maintenance HD patients. Methods: This was a single-center cross-sectional study conducted between March 2018 and March 2019 at the Department of Blood Purification, Beijing Chao-Yang Hospital, Capital Medical University. One hundred and fifteen HD patients were enrolled. Clinical data on demographics, comorbidities, and the primary cause of end-stage renal disease were obtained by questionnaires. Laboratory data were collected pre- and post-HD. Participants were divided into 3 groups according to PDF degree. Results: The prevalence of PDF in participants was 60% ( n = 69); 26.09% had mild PDF; and 33.91% had severe PDF. In the severe PDF group, the prevalence of intradialytic hypotension (IDH) was 38.46%, significantly higher than in the no PDF group (no-PDF; 8.70%) and mild-PDF (16.67%; p = 0.01 for both) groups. In the severe-PDF group, Charlson comorbidity index score and ultrafiltration rate were significantly higher than those in the no-PDF group ( p = 0.040, p = 0.020, respectively). In the severe-PDF group, postdialysis lactic acid (Lac) level was significantly higher than that in the no-PDF or mild-PDF groups ( p = 0.013 for both). And in the severe-PDF group, postdialysis sodium (Na) was significantly lower than that in the no-PDF or mild-PDF groups ( p = 0.026 for both). It was shown by unconditional logistic regression analysis that IDH occurrence (OR 3.821, 95% CI 1.330–10.975), ultrafiltration rates (OR 1.142, 95% CI 1.018–1.281), lower postdialysis Na level (OR 0.724, 95% CI 0.556–0.942), and higher postdialysis Lac level (OR 2.465, 95% CI 1.126–5.397) were associated with PDF ( p = 0.013, p = 0.024, p = 0.016, and p = 0.024, respectively). Conclusions: The prevalence of PDF was high among our study participants. PDF incidence was correlated with the IDH occurrence and higher postdialysis Lac and lower postdialysis Na levels. The level of Lac was a significant influencing factor for the fatigue of patients. More attention should thus be paid to PDF.