Fusarium Head Blight of small-grain cereals is a devastating fungal disease primarily caused by Fusarium graminearum in Europe that affects crops worldwide. Beyond crop losses, F. graminearum poses potential health risks due to the production of mycotoxins. In the context of lowering the dependency on agrochemicals, the development of environmental-friendly strategies is of great importance to guarantee the safety of food and feed. One of these strategies lies on the promising capacity of compounds issued from natural sources to counteract phytopathogens. In this work, the in vitro efficiency of 13 eco-extracts obtained from grapevine by-products was assessed against fungal growth and mycotoxin production by F. graminearum. To identify the compounds responsible for this bioactivity, a strategy combining untargeted metabolomics and bioguided fractionation was implemented and has led to evidence the key contribution of oligomeric stilbenes. The antifungal and antimycotoxin activity of stilbenes was then confirmed, using pure molecules (resveratrol/RES, a monomer and vitisin B/VIT B, a tetramer). The higher efficacy of VIT B compared to that of RES was demonstrated. To deeper the knowledge on the mode of action of stilbenes, multi-omics approaches associating mRNA-seq-based transcriptomics and LC-MS/MS-based non-targeted metabolomics have been conducted. Altogether, our data support, on the one hand, the power of metabolomics approaches to identify active molecules occurring in natural extracts and to study their mechanisms of action and, on the second hand, that grapevine by-products could be promising sustainable sources of bioactive compounds for controlling F. graminearum and minimizing the contamination of cereals with mycotoxins.