Key point PGC‐1α pathway activation has been shown to decrease disease severity and can be driven by quercetin. Oral quercetin supplementation protected respiratory function for 4–6 months during a 12 month dosing regimen. This transient protection was probably due to a failure to sustain elevated SIRT1 activity and downstream PGC‐1α signalling. Quercetin supplementation may be a beneficial treatment as part of a cocktail provided continued SIRT1 activity elevation is achieved. Abstract Duchenne muscular dystrophy (DMD) impacts 1 : 3500 boys and leads to muscle dysfunction culminating in death due to respiratory or cardiac failure. There is an urgent need for effective therapies with the potential for immediate application for this patient population. Quercetin, a flavonoid with an outstanding safety profile, may provide therapeutic relief to DMD patients as the wait for additional therapies continues. This study evaluated the capacity of orally administered quercetin (0.2%) in 2 month old mdx mice to improve respiratory function and end‐point functional and histological outcomes in the diaphragm following 12 months of treatment. Respiratory function was protected for the first 4–6 months of treatment but appeared to become insensitive to quercetin thereafter. Consistent with this, end‐point functional measures were decreased and histopathological measures were more severe in dystrophic muscle compared to C57 and similar between control‐fed and quercetin‐fed mdx mice. To better understand the transient nature of improved respiratory function, we measured PGC‐1α pathway activity, which is suggested to be up‐regulated by quercetin supplementation. This pathway was largely suppressed in dystrophic muscle compared to healthy muscle, and at the 14 month time point dietary quercetin enrichment did not increase expression of downstream effectors. These data support the efficacy of quercetin as an intervention for DMD in skeletal muscle, and also indicate the development of age‐dependent quercetin insensitivity when continued supplementation fails to drive the PGC‐1α pathway. Continued study is needed to determine if this is related to disease severity, age or other factors.