Melon (Cucumis melo L.) is the model species of the Cucurbitaceae family and an important crop, with an estimated production at 28 million tonnes in 2020. However, its yield is primarily affected by viruses. Cucumber mosaic virus (CMV) is particularly significant due to its broad host range, capable of infecting over 100 plant families. Resistance to CMV in the melon accession Songwhan Charmi (SC) is controlled by the recessive gene cmv1, which encodes the Vacuolar Protein Sorting 41, involved in vesicle transport to the vacuole. cmv1 restricts the virus to the bundle sheath cells and impedes viral access to the phloem, and this phenotype depends on the viral movement protein (MP). However, little is known about the broader cellular changes that CMV triggers in melon or the specific biological responses that facilitate or restrict the virus' entry into the phloem in susceptible and resistant varieties. We profiled the proteomes of CMV-resistant or susceptible melon genotypes inoculated with LS or FNY strains. Analysis of co-abundance networks revealed pathways involved in CMV resistance and susceptibility at different infection stages. Upon inoculation, resistant varieties have stronger changes in proteome composition compared to susceptible varieties, including an increase in lipid signalling and upregulation of phloem defence proteins. In contrast, susceptible melon plants displayed fewer proteins related to translation, photosynthesis and intracellular transport. During the systemic infection of susceptible melon plants, proteins associated with stress responses increase, such as those involved in the ER-associated degradation (ERAD) and phenylpropanoid pathways. Collectively, our study shed new light on the interactions between CMV and melon plants.