The catabolism of fatty acid (FA) is regarded as a key pathway of aroma volatile compounds in oriental sweet melon (Cucumis melo var. makuwa). In our research, two cultivars of oriental sweet melon, Caihong7 and Tianbao, were employed to illuminate which step of the biosynthetic pathway of aroma compounds could be regulated by ethylene (ETH). The role of ETH in determining the profiles of straight-chain aroma volatile compounds, levels of FA as aroma precursors, activities of aroma-related enzymes derived from FA pathway, and expression patterns of key enzymes were investigated. Overall, exogenous application of ETH increased the production rates of endogenous ETH and levels of FA. Compared with control, the level of straight-chain esters, especially the acetate, hexanoate, and hexyl esters, was significantly increased by ETH, whereas the content of alcohol and aldehyde reduced. In addition, the metabolism of free FA included linoleic acid (LA), linolenic acid (LeA), and oleic acid (OA) appeared to be ETH-dependent. The activities of lipoxygenase (LOX), alcohol dehydrogenase (ADH), and alcohol acetyltransferase (AAT) as well as the expression patterns of Cm-ADH1, Cm-ADH2, Cm-AAT1, and Cm-AAT4 were positively regulated by ETH. In contrast, hydroperoxide lyase (HPL) and Cm-AAT2 and Cm-AAT3 seemed to be independent of ETH modulation. These results suggested that the dissimilation of FA included LA, LeA, and OA into the acetate, hexanoate, and hexyl esters mainly through ETH regulating the LOX pathway by enhancing the expression of particular members of aroma-related key enzyme gene families as well as the activities of dehydrogenation and esterification.