Consumption of a post-exercise protein-polyphenol supplement accelerates recovery of muscle function after maximal eccentric contractions (EC), likely due to increased muscle protein turnover and/or reduced inflammation. Here we investigate the differences in transcriptional events that occur during recovery with protein-polyphenol supplementation to provide novel understanding in to the mechanisms by which this is mediated. Eighteen young, recreationally active participants (age: 22 ± 1 y; BMI: 24.3 ± 0.8 kg.m-2) performed 300 maximal unilateral quadriceps EC on day 7 of a 14-day protocol, followed by daily assessment of isokinetic concentric work (IC). Supplements providing 20 g protein from a blend of whey, casein, and pea, and 650 mg pomegranate extract (Beachbody LLC, USA; PRO; n = 9; 3 females) or an isocaloric carbohydrate placebo (PLA; n = 9; 4 females) were consumed daily, alongside full dietary control providing 1.2 g.kg-1 of protein. RNA was isolated from muscle biopsy samples obtained at 24, 27, 36, 72 and 168 h post EC and reverse transcribed into cDNA. Transcriptional expression of 224 genes associated with skeletal muscle metabolism were assessed by RT-PCR. IC data were measured relative to the contralateral leg (%con). Gene expression data were normalised to α-actin and β2-microglobulin, and to the control leg of a PLA subject, using the 2-(ΔΔCt) method. Two-way ANOVAs were used to analyse the data, with the alpha level for transcriptional changes informed by a prior Significance Analysis for Microarrays calculation (FDR<1%). Gene ontology analysis of differentially expressed genes was performed against the KEGG pathway (DAVID 6.8, NIH). The original gene list was used as a background for the enrichment analysis to eliminate bias from the selection of genes. Eccentric exercise reduced IC to 67.6 ± 5.9 %con at 48 h in PLA, which remained suppressed for 120 h (P<0.05). Conversely in PRO, IC dropped to 78.3 ± 7.2%con at 24 h (P<0.01) and had recovered by 48 h (P>0.05). Expression of 68 genes changed over time following EC (n = 7 per group; time effect; P<0.01), with mean expression reducing linearly from 19.3 ± 5.4-fold at 24 h to 3.3 ± 0.4-fold 168 h post-EC. Between PLA and PRO, 112 genes were differentially expressed (group effect; P<0.01), with ‘mTOR signaling’ the most enriched pathway in gene ontology analysis. Over time, 26 genes were expressed divergently between PLA and PRO (interaction effect; P<0.01), with ‘Hippo signaling’ pathway the most enriched. EC induces a rapid, robust change in skeletal muscle gene expression that is associated with reduced muscle function. Consumption of a protein-polyphenol supplement following EC alters this response and is associated with improved recovery, likely via protein synthesis (mTOR) and regulation of turnover (Hippo) pathways.