ABSTRACT: The root-endophytic fungus Piriformospora indica (=Serendipita indica) has been revealed for its growth-promoting effects and its capacity to induce resistance in a broad spectrum of host plants. However, the bioefficacy of this fungus had not yet been tested against any pathogen affecting onion (Allium cepa). In this study, the biocontrol potency of P. indica against onion leaf blight, an impacting disease caused by the necrotrophic fungal pathogen Stemphylium vesicarium, was evaluated. First, it was proved that colonisation of onion roots by P. indica was beneficial for plant growth, as it increased leaf development and root biomass. Most relevantly, P. indica was also effective in reducing Stemphylium leaf blight (SLB) severity, as assessed under greenhouse conditions and confirmed in field trials in two consecutive years. These investigations could also provide some insight into the biochemical and molecular changes that treatment with P. indica induces in the main pathways associated with host defence response. It was possible to highlight the protective effect of P. indica colonisation against peroxidative damage, and its role in signalling oxidative stress, by assessing changes in malondialdehyde and H2O2 content. It was also showed that treatment with P. indica contributes to modulate the enzymatic activity of superoxide dismutase, catalase, phenylalanine ammonia-lyase and peroxidase, in the course of infection. qPCR-based expression analysis of defence-related genes AcLOX1, AcLOX2, AcPAL1, AcGST, AcCHI, AcWRKY1, and AcWRKY70 provided further indications on P. indica ability to induce onion systemic response. Based on the evidence gathered, this study aims to propose P. indica application as a sustainable tool for improving SLB control, which might not only enhance onion growth performance but also activate defence signalling mechanisms more effectively, involving different pathways.