The high metastatic potential of melanoma and its poor prognosis in advanced stages motivate the search for innovative therapeutic approaches. Therefore, this study aimed to assess the effects of phytocannabinoids (cannabidiol-CBD, and cannabigerol-CBG) on the structure and function of the melanoma cell membrane, phospholipid metabolism, and the respective metabolites generated in ROS- and enzyme-dependent reactions. Biochemical and physicochemical parameters were analyzed in melanoma cells (SK-MEL-5) cultured for 24 h with CBD (5 µM), CBG (1 µM), and their combination applied either alone or after UVA irradiation (365 nm) at a dose of 18 J/cm². Phytocannabinoids have been shown to partially counteract changes in the levels of cell membrane components, including phospholipid polyunsaturated fatty acids (PUFAs) and sialic acid, consequently affecting surface charge density and lipid rafts, which may be a potential target for anticancer therapy. Furthermore, by changing the activity of lipolytic enzymes (PLA2/COX1/2/LOX-5), phytocannabinoids partially enhanced the UVA-induced decrease in free PUFAs. Consequently, the levels of lipid mediators, including endocannabinoids and eicosanoids, were altered. The use of phytocannabinoids led to a significant increase in 2-AG levels, while the combined action of CBD/CBG reduced the levels of pro-inflammatory eicosanoids. UVA radiation increased the expression of G-protein-coupled receptors in melanoma cells (CB1/2/TRPV1/PPARγ), while the combined use of CBD/CBG reduced their expression. Therefore, the results have shown that CBD and CBG modulate the metabolism of phospholipids and PUFAs by altering the functions of melanoma cell membranes, potentially offering options for the use of these phytocannabinoids in the integrative biomedicine treatment of melanoma.