Monitoring meat quality characteristics with accurate and non-invasive tools to detect, before slaughter, animals with desired quality characteristics, is a prerequisite of meat industry. Plasma, as a readily available biofluid, represents a potential biological source of information about the animal's physiological and pathological condition, as well as its underlying biological mechanisms. In this regard, a proteomics approach on plasma and muscle proteomes were applied to assess the effect of two different dietary treatments on in vita biological processes and meat quality. Twenty-two Valle del Belice male lambs were randomly assigned to two dietary treatment groups. Control group (C) received a maize-barley without any supplement, whereas the hazelnut group (H), received a hazelnut skin by-product as a maize partial replacer in the concentrate diet. The results revealed that hazelnut skin by-product dietary supplementation impacted meat quality characteristics, with meat from lamb of the H group displaying greater values of lightness, redness, yellowness, and chroma color parameters together with greater myofibril fragmentation index. Proteomic and bioinformatics approaches applied to plasma proteome revealed twenty protein spots (18 unique gene names) belonging to ‘enzyme regulator activity’ including serpins, ‘identical protein binding’, ‘antioxidant activity’, ‘steroid binding’ and ‘cholesterol transfer activity’ as differentially expressed due to hazelnut skin by-product supplementation. Twenty-three proteins from the muscle proteome of known roles in post-mortem processes, likely ‘muscle contraction, structure, and associated proteins’, ‘energy metabolism’, ‘heat shock proteins’, ‘oxidative stress’ and ‘immunity, binding & transport proteins’ could act as potential predictors of lamb meat quality. To clear up the complex relationships between plasma and muscle proteomes of the two dietary groups, comparative bioinformatics revealed APOA1, PHB, ACTG1, and ALB as common proteins, hence suggesting sophisticated biological crosstalk and potential use as candidate biomarkers to monitor lamb meat quality production. Our findings underline the important role of plasma as a challenging biofluid protein source to predict in a non-invasive manner the lamb meat quality.