Studies suggest that hemodialysis patients are at a higher risk for cognitive decline than healthy individuals; however, underlying mechanisms have not been fully elucidated. We aimed to investigate the roles of serum biomarkers, such as brain-derived neurotrophic factor (BDNF), inflammatory cytokines, fibroblast growth factor (FGF)-23 and its co-receptor α-klotho and platelet (PLT) count in mild cognitive decline (MCD) of patients undergoing hemodialysis in this prospective cohort study. Serum levels of BDNF, tumour necrosis factor (TNF)-α, interleukin (IL)-6 and the number of PLT were significantly altered in the MCD group compared with those in healthy controls (HCs) or those with normal cognitive function (NCF). Although serum α-klotho and FGF-23 levels were significantly altered in the MCD group, there were no statistical differences between the MCD and NCF groups. Serum BDNF levels and PLT counts were significantly correlated with cognitive test scores. Receiver operating characteristic (ROC) curves demonstrated that BDNF and PLT were potential biomarkers for improved MCD diagnosis in patients with hemodialysis. These findings suggest that hemodialysis-related MCD is associated with altered BDNF, TNF-α and IL-6 levels as well as PLT counts and that serum BDNF levels and PLT counts are potential biomarkers for hemodialysis-related MCD diagnosis.