Melatonin (MT) is a vital hormone factor in plant growth and development, yet its potential to influence the graft union healing process has not been reported. In this study, we examined the effects of MT on the healing of oriental melon scion grafted onto squash rootstock. The studies indicate that the exogenous MT treatment promotes the lignin content of oriental melon and squash stems by increasing the enzyme activities of hydroxycinnamoyl CoA ligase (HCT), hydroxy cinnamaldehyde dehydrogenase (HCALDH), caffeic acid/5-hydroxy-conifer aldehyde O-methyltransferase (COMT), caffeoyl-CoA O-methyltransferase (CCoAOMT), phenylalanine ammonia-lyase (PAL), 4-hydroxycinnamate CoA ligase (4CL), and cinnamyl alcohol dehydrogenase (CAD). Using the oriental melon and squash treated with the exogenous MT to graft, the connection of oriental melon scion and squash rootstock was more efficient and faster due to higher expression of wound-induced dedifferentiation 1 (WIND1), cyclin-dependent kinase (CDKB1;2), target of monopteros 6 (TMO6), and vascular-related NAC-domain 7 (VND7). Further research found that the exogenous MT increased the lignin content of the oriental melon scion stem by regulating CmCAD1 expression, and then accelerated the graft healing process. In addition, the root growth of grafted seedlings treated with the exogenous MT was more vigorous.