Objective To explore the role of the forkhead box O3a（FOXO3a）/nuclear factor erythroid 2-related factor 2（Nrf2） signaling pathway in regulating skeletal muscle autophagy in uremia. Methods Twenty-four mice were randomly divided into sham group，chronic kidney disease（CKD） group，and CKD+AST-120（AST） group，with eight mice in each group. A CKD model was established by using the 5/6 nephrectomy method. Four weeks after nephrectomy，the mice in the CKD+AST group were fed with powder chow containing AST-120（a charcoal adsorbent for uremic toxin） for eight weeks. Autolysosomes in the gastrocnemius muscle were observed using a transmission electron microscope. C2C12 myoblasts were divided into control group，indophenol sulfate group（IS），and IS+si-FOXO3a group. The expression of FOXO3a was determined using real-time RT-PCR and Western blot. The diameter of C2C12 myotubes was measured with Giemsa staining. Results Compared with the CKD group，the CKD+AST group showed significant decreases in serum IS level and FOXO3a expression and the number of autolysosomes in the gastrocnemius tissue and significant increases in the masses of the gastrocnemius muscle，anterior tibial muscle，and soleus muscle（all P<0.05）. Compared with the IS group，the IS+si-FOXO3a group showed significant reductions in the expression of FOXO3a，atrogin-1，and muscle RING-finger protein-1 in C2C12 cells as well as the autophagic flux of the cells and a significantly increased cell diameter（all P<0.05）. Compared with the sham group，the CKD group showed significantly increased expression of Kelch-like ECH-associated protein 1（KEAP1） and significantly decreased Nrf2 expression in the gastrocnemius tissue（both P<0.05）. AST treatment reversed the changes in these proteins in the gastrocnemius tissue of CKD mice. Si-Nrf2 reversed the inhibitory effect of FOXO3a knockdown on autophagic flux. Conclusion IS may promote skeletal muscle autophagy by continuously stimulating the FOXO3A-KEAP1-Nrf2 axis to participate in the pathogenesis of uremic sarcopenia.