Objectives: Anemia is a common complication of chronic kidney disease (CKD). However, it is difficult to assess the effect of renal anemia in CKD patients on long-term outcomes, such as mortality and morbidity, because kidney function affects outcomes directly and indirectly. This study evaluated the mediating effect of anemia in the relationship between CKD and clinical outcomes. Methods: We used NHANES data from 1999 through 2014 and included adults aged ≥ 20 years. The percent mediating effect of four biomarkers indicative of anemia (hemoglobin [Hb], hematocrit [Hct], red cell distribution width [RDW], and mean corpuscular hemoglobin concentration [MCHC]) was examined by comparing the hazard ratios from a biomarker-adjusted model. Results: Of the 38,951 participants, all-cause death occurred in 4,997. Cox proportional hazard models revealed a higher risk of all-cause mortality in the > 45 years and CKD groups than in the early CKD group. Together, the levels of Hb and Hct were inversely related to all-cause mortality, and RDW was related to mortality. The single mediation analysis showed that the mediation effects of anemia indicators on CKD and all-cause mortality in the elderly (> 65 years) population were greater than those in the general population. Similarly, in the multimediation analysis, the combined mediation effect of anemia was higher in the elderly (> 65 years) and CKD group than in the general population. Conclusions: This study showed that the mediating effects of anemia increased proportionally to age and the CKD stage. Additionally, we suggest possible mechanism of anemia on CKD, which shed light on a new therapeutic ways although it is necessary to explore the effects of other potential mediating factors on kidney outcomes.