The leafy green vegetable Lactuca sativa, L. is susceptible to the soil-born fungus Rhizoctonia solani AG1-IB. In a previous study, we reported on the transcriptional response of R. solani AG1-IB (isolate 7/3/14) during the interspecies interaction with L. sativa cv. Tizian by means of RNA sequencing. Here we present the L. sativa transcriptome and metabolome from the same experimental approach. Three distinct interaction zones were sampled and compared to a blank (non-inoculated) sample: symptomless zone 1, zone 2 showing light brown discoloration, and a dark brown zone 3 characterized by necrotic lesions. Throughout the interaction, we observed a massive reprogramming of the L. sativa transcriptome, with 9231 unique genes matching the threshold criteria for differential expression. The lettuce transcriptome of the light brown zone 2 presents the most dissimilar profile compared to the uninoculated zone 4, marking the main stage of interaction. Transcripts putatively encoding several essential proteins that are involved in maintaining jasmonic acid and auxin homeostasis were found to be negatively regulated. These and other indicator transcripts mark a potentially inadequate defence response, leading to a compatible interaction. KEGG pathway mapping and GC-MS metabolome data revealed large changes in amino acid, lignin and hemicellulose related pathways and related metabolites.