Abstract Background Mild cognitive impairment (MCI) occurs frequently in many end stage renal disease (ESRD) patients, may significantly worsen survival odds and prognosis. However, the exact neuropathological mechanisms of MCI combined with ESRD are not fully clear. This study examined functional connectivity (FC) alterations of the default-mode network (DMN) in individuals with ESRD and MCI. Methods Twenty–four individuals with ESRD identified as MCI patients were included in this study; of these, 19 and 5 underwent hemodialysis (HD) and peritoneal dialysis (PD), respectively. Another group of 25 age-, sex- and education level-matched subjects were recruited as the control group. All participants underwent resting-state functional MRI and neuropsychological tests; the ESRD group underwent additional laboratory testing. Independent component analysis (ICA) was used for DMN characterization. With functional connectivity maps of the DMN derived individually, group comparison was performed with voxel-wise independent samples t-test, and connectivity changes were correlated with neuropsychological and clinical variables. Results Compared with the control group, significantly decreased functional connectivity of the DMN was observed in the posterior cingulate cortex (PCC) and precuneus (Pcu), as well as in the medial prefrontal cortex (MPFC) in the ESRD group. Functional connectivity reductions in the MPFC and PCC/Pcu were positively correlated with hemoglobin levels. In addition, functional connectivity reduction in the MPFC showed positive correlation with Montreal Cognitive Assessment (MoCA) score. Conclusion Decreased functional connectivity in the DMN may be associated with neuropathological mechanisms involved in ESRD and MCI.