The melon (Cucumis melo L.) is a globally cherished and economically significant crop. The grafting technique has been widely used in the vegetative propagation of melon to promote environmental tolerance and disease resistance. However, mechanisms governing graft healing and potential incompatibilities in melons following the grafting process remain unknown. To uncover the molecular mechanism of healing of grafted melon seedlings, melon wild type (Control) and TRV‐CmGH9B3 lines were obtained and grafted onto the squash rootstocks (C. moschata). Anatomical differences indicated that the healing process of the TRV‐CmGH9B3 plants was slower than that of the control. A total of 335 significantly differentially expressed genes (DEGs) were detected between two transcriptomes. Most of these DEGs were down‐regulated in TRV‐CmGH9B3 grafted seedlings. GO and KEGG analysis showed that many metabolic, physiological, and hormonal responses were involved in graft healing, including metabolic processes, plant hormone signaling, plant MAPK pathway, and sucrose starch pathway. During the healing process of TRV‐CmGH9B3 grafted seedlings, gene synthesis related to hormone signal transduction (auxin, cytokinin, gibberellin, brassinolide) was delayed. At the same time, it was found that most of the DEGs related to the sucrose pathway were down‐regulated in TRV‐CmGH9B3 grafted seedlings. The results showed that sugar was also involved in the healing process of melon grafted onto squash. These results deepened our understanding of the molecular mechanism of GH9B3, a key gene of β‐1, 4‐glucanase. It also provided a reference for elucidating the gene mechanism and function analysis of CmGH9B3 in the process of graft union healing.