Obesity is caused by lipid accumulation in adipose tissues inducing adipocyte dysfunction, characterized by insulin resistance, increased lipolysis, oxidative stress, and inflammation, leading to increased levels of adipokines. Herein the capacity of the subfractions (SFs) SF1, SF2, and SF3 from the Cucumis sativus aqueous fraction and their combinations (M) to control adipocyte dysfunction in vitro, in 3T3-L1 adipocytes was studied. Adipocytes, previously treated with dexamethasone or IL-1 to induce dysfunction, were incubated with different concentrations of the subfractions for 24 h. 2-deoxyglucose consumption and glycerol release were evaluated, and a surface model was constructed to determine the most effective SF concentrations to improve both parameters. Effective SF combinations were assessed in their capacity to control metabolic, pro-oxidative, and pro-inflammatory conditions. SF1, SF2 (40 μg/ml each) and SF3 (20 μg/ml) improved 2-deoxyglucose consumption by 87%, 57%, and 87%, respectively. SF1 and SF2 (5 μg/ml each) and SF3 (40 μg/mL) increased glycerol secretion by 10.6%, 18.9%, and 11.8%, respectively. Among five combinations tested, only M4 (SF1 40 μg/ml:SF2 60 μg/ml:SF3 30 μg/ml) and M5 (SF1 40 μg/ml:SF2 60 μg/mL:SF3 10 μg/ml) controlled effectively the metabolic, pro-oxidative, and proinflammatory conditions studied. Glycine, asparagine, and arginine were the main components in these SFs.