Gummy stem blight (GSB), a severe and widespread disease causing great losses to cucurbit production, is a major threat to melon production. However, the melon-GSB interaction remains largely unknown, which significantly impedes the genetic improvement of melon for GSB resistance. Here, full-length transcriptome and widely targeted metabolome were used to reveal the early defense responses of resistant (PI511890) and susceptible (Payzawat) melon to GSB. Differentially expressed genes were specifically enriched in the secondary metabolite biosynthesis and MAPK signaling pathway in PI511890, while in carbohydrate metabolism and amino acid metabolism in Payzawat. More than 1000 novel genes were identified in PI511890, which were enriched in the MAPK signaling pathway. There were 11,793 alternative splicing events identified and involved the defense response to GSB. A total of 910 metabolites were identified, with flavonoids as the dominant metabolites. Integrated full-length transcriptome and metabolome analysis showed that eriodictyol and oxalic acid may be used as marker metabolites for GSB resistance in melon. Moreover, post-transcription regulation was widely involved in the defense response of melon to GSB. These results improve our understanding of the interaction between melon and GSB and may facilitate the genetic improvement of GSB resistance of melon.