Fomitiporia mediterranea M. Fischer (Fmed) is a white-rot wood-decaying fungus associated with one of the most important and challenging diseases in vineyards: Esca. To relieve microbial degradation, woody plants, including Vitis vinifera, use structural and chemical weapons. Lignin is the most recalcitrant of the wood cell wall structural compounds and contributes to wood durability. Extractives are constitutive or de novo synthesized specialized metabolites that are not covalently bound to wood cell walls and are often associated with antimicrobial properties. Fmed is able to mineralize lignin and detoxify toxic wood extractives, thanks to enzymes such as laccases and peroxidases. Grapevine wood’s chemical composition could be involved in Fmed’s adaptation to its substrate. This study aimed at deciphering if Fmed uses specific mechanisms to degrade grapevine wood structure and extractives. Three different wood species, grapevine, beech, and oak. were exposed to fungal degradation by two Fmed strains. The well-studied white-rot fungus Trametes versicolor (Tver) was used as a comparison model. A simultaneous degradation pattern was shown for Fmed in the three degraded wood species. Wood mass loss after 7 months for the two fungal species was the highest with low-density oak wood. For the latter wood species, radical differences in initial wood density were observed. No differences between grapevine or beech wood degradation rates were observed after degradation by Fmed or by Tver. Contrary to the Tver secretome, one manganese peroxidase isoform (MnP2l, jgi protein ID 145801) was the most abundant in the Fmed secretome on grapevine wood only. Non-targeted metabolomic analysis was conducted on wood and mycelium samples, using metabolomic networking and public databases (GNPS, MS-DIAL) for metabolite annotations. Chemical differences between non-degraded and degraded woods, and between mycelia grown on different wood species, are discussed. This study highlights Fmed physiological, proteomic and metabolomic traits during wood degradation and thus contributes to a better understanding of its wood degradation mechanisms.