Numerous studies have highlighted the strong association between reduced incidence of chronic diseases and diets rich in fruits and vegetables, which are abundant sources of bioactive compounds. Among these, carotenoids have garnered significant attention for their potential to modulate and prevent metabolic dysfunctions. In this study, we investigated the nutraceutical potential of a β-cryptoxanthin-rich carotenoid extract obtained from persimmon (Diospyros kaki Thunb.) by-products. High-performance liquid chromatography (HPLC) confirmed the carotenoid profile of the extract, with β-cryptoxanthin as the major compound. In vitro assays using 3T3-L1 murine adipocytes demonstrated that the extract reduced reactive oxygen species (ROS) and intracellular triglyceride accumulation without cytotoxic effects. In vivo, C57BL/6J mice were fed either a high-fat diet (HFD) or a low-fat diet (LFD), both with or without extract supplementation, over 12 weeks. The extract significantly reduced serum triglycerides, total cholesterol, LDL-cholesterol, and pro-inflammatory cytokines, while improving HDL-cholesterol levels. Hepatic tissue analysis revealed a marked reduction in collagen deposition and lipid accumulation in HFD-treated mice, indicating hepatoprotective effects. Furthermore, in silico docking suggested a potential interaction of β-cryptoxanthin with ADIPOR and GLUT1 receptors, possibly underlying the observed metabolic improvements. Collectively, these findings support the application of β-cryptoxanthin-rich persimmon extract as a promising nutraceutical strategy to combat obesity and metabolic-associated fatty liver disease (MAFLD). Further studies are warranted to confirm its efficacy in clinical settings.