Abstract Background The non-climacteric ‘Yellow’ melon (Cucumis melo, inodorus group) is an economically important crop and its quality is mainly determined by the sugar content. Thus, knowledge of sugar metabolism and its related pathways can contribute to the development of new field management and post-harvest practices, making it possible to deliver better quality fruits to consumers. Results The RNA-seq associated with RT-qPCR analyses of four maturation stages were performed to identify important enzymes and pathways that are involved in the ripening profile of non-climacteric ‘Yellow’ melon fruit focusing on sugar metabolism. We identified 895 genes 10 days after pollination (DAP)-biased and 909 genes 40 DAP-biased. The KEGG pathway enrichment analysis of these differentially expressed (DE) genes revealed that ‘hormone signal transduction’, ‘carbon metabolism’, ‘sucrose metabolism’, ‘protein processing in endoplasmic reticulum’ and ‘spliceosome’ were the most differentially regulated processes occurring during melon development. In the sucrose metabolism, five DE genes are up-regulated and 12 are down-regulated during fruit ripening. Conclusions The results demonstrated important enzymes in the sugar pathway that are responsible for the sucrose content and maturation profile in non-climacteric ‘Yellow’ melon. New DE genes were first detected for melon in this study such as invertase inhibitor LIKE 3 (CmINH3), trehalose phosphate phosphatase (CmTPP1) and trehalose phosphate synthases (CmTPS5, CmTPS7, CmTPS9). Furthermore, the results of the protein-protein network interaction demonstrated general characteristics of the transcriptome of young and full-ripe melon and provide new perspectives for the understanding of ripening.