Catabolic conditions like chronic kidney disease (CKD) cause loss of muscle mass by unclear mechanisms. In muscle biopsies from CKD patients, we found activated Stat3 (p-Stat3) and hypothesized that p-Stat3 initiates muscle wasting. We created mice with muscle-specific knockout (KO) that prevents activation of Stat3. In these mice, losses of body and muscle weights were suppressed in models with CKD or acute diabetes. A small-molecule that inhibits Stat3 activation produced similar responses, suggesting a potential for translation strategies. Using CCAAT/enhancer-binding protein delta (C/EBP delta) KO mice and C2C12 myotubes with knockdown of C/EBPd or myostatin, we determined that p-Stat3 initiates muscle wasting via C/EBP delta, stimulating myostatin, a negative muscle growth regulator. C/EBP delta KO also improved survival of CKD mice. We verified that p-Stat3, C/EBP delta, and myostatin were increased in muscles of CKD patients. The pathway from p-Stat3 to C/EBP delta to myostatin and muscle wasting could identify therapeutic targets that prevent muscle wasting.