Patients with chronic heart failure (CHF) experience exercise intolerance, fatigue and muscle wasting, which negatively influence their survival. We hypothesized that treatment with either the antioxidant N‐acetyl cysteine (NAC) or the proteasome inhibitor bortezomib of rats with monocrotaline‐induced CHF may restore inspiratory and limb muscle mass, function, and structure through several molecular mechanisms involved in protein breakdown and metabolism in the diaphragm and gastrocnemius. In these muscles of CHF‐cachectic rats with and without treatment with NAC or bortezomib (N = 10/group) and non‐cachectic controls, proteolysis (tyrosine release, proteasome activities, ubiquitin‐proteasome markers), oxidative stress, inflammation, mitochondrial function, myosin, NF‐κB transcriptional activity, muscle structural abnormalities, and fiber morphometry were analyzed together with muscle and cardiac functions. In diaphragm and gastrocnemius of CHF‐cachectic rats, tyrosine release, proteasome activity, protein ubiquitination, atrogin‐1, MURF‐1, NF‐κB activity, oxidative stress, inflammation, and structural abnormalities were increased, while muscle and cardiac functions, myosin content, slow‐ and fast‐twitch fiber sizes, and mitochondrial activity were decreased. Concomitant treatment of CHF‐cachectic rats with NAC or bortezomib improved protein catabolism, oxidative stress, inflammation, muscle fiber sizes, function and damage, superoxide dismutase and myosin levels, mitochondrial function (complex I, gastrocnemius), cardiac function and decreased NF‐κB transcriptional activity in both muscles. Treatment of CHF‐cachectic animals with NAC or bortezomib attenuated the functional (heart, muscles), biological, and structural alterations in muscles. Nonetheless, future studies conducted in actual clinical settings are warranted in order to assess the potential beneficial effects and safety concerns of these pharmacological agents on muscle mass loss and wasting in CHF‐cachectic patients. J. Cell. Physiol. 231: 1495–1513, 2016. © 2015 Wiley Periodicals, Inc.