<p>Chronic kidney disease (CKD) and peripheral artery disease (PAD) frequently coexist and synergistically exacerbate skeletal muscle dysfunction, contributing to limb function impairment and increased risk of amputation and mortality. Both diseases independently promote fibrotic remodeling in muscle, suggesting that anti-fibrotic therapies may improve muscle health in this high-risk population. We tested whether targeting the fibrotic niche with batimastat, a matrix metalloprotease inhibitor, or pirfenidone, an approved anti-fibrotic medication, would improve ischemic limb function in a mouse model of CKD and PAD. Male mice (<i>n</i> = 21) were fed an adenine diet to induce CKD and subsequently underwent surgical femoral artery ligation to induce hindlimb ischemia, an experimental model of PAD. Pirfenidone significantly improved ischemic muscle absolute force (<i>P</i> &lt; 0.0001) and specific force (<i>P</i> = 0.0027), and increased time-tension integral during a muscle fatigue test (<i>P</i> &lt; 0.0001), while batimastat significantly reduced these parameters compared to placebo. Surprisingly, neither treatment altered muscle fibrosis, perfusion recovery, capillary density, or myofiber regeneration, indicating that functional improvements with pirfenidone occurred independently of structural remodeling. These findings suggest that pirfenidone preserves muscle strength and quality and may have therapeutic potential to improve limb function in patients with CKD and PAD. Further investigation is warranted to define pirfenidone’s mechanism of action in skeletal muscle and evaluate its efficacy in the clinical setting.</p>