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Abstract Background Muscle wasting is a common complication of chronic kidney disease (CKD) that is associated with higher mortality. Although the mechanisms of myofibre loss in CKD has been widely studied, the contribution of muscle precursor cell (MPC) senescence remains poorly understood. Senescent MPCs no longer proliferate and can produce proinflammatory factors or cytokines. In this study, we tested the hypothesis that the senescence associated secretory phenotype (SASP) of MPCs contributes to CKD‐induced muscle atrophy and weakness. Methods CKD was induced in mice by 5/6th nephrectomy. Kidney function, muscle size, and function were measured, and markers of atrophy, inflammation, and senescence were evaluated using immunohistochemistry, immunoblots, or qPCR. To study the impact of senescence, a senolytics cocktail of dasatinib + quercetin (D&Q) was given orally to mice for 8 weeks. To investigate CKD‐induced senescence at the cellular level, primary MPCs were incubated with serum from CKD or control subjects. The roles of specific proteins in MPC senescence were studied using adenoviral transduction, siRNA, and plasmid transfection. Results In the hindlimb muscles of CKD mice, (i) the senescence biomarker SA‐β‐gal was sharply increased (~30‐fold); (ii) the DNA damage response marker γ‐H2AX was increased 1.9‐fold; and (iii) the senescence pathway markers p21 and p16INK4a were increased 1.99‐fold and 2.82‐fold, respectively (all values, P