Obesity is widely associated with intestine barrier impairment, nonalcoholic fatty liver disease (NAFLD) outbreaks, oxidative stress, and inflammation. In a previous investigation, the Solanum aethiopicum L. growing in Basilicata Region has demonstrated to have antioxidant activity; hence this investigation was aimed to evaluate for the first time the antilipidemic and anti-inflammatory activity of the Lucanian S. aethiopicum L. peel extract in vitro on OA-treated HepG2 and Caco-2 cell lines. It was shown that the extract could reduce lipogenesis by down-regulating SREBP-1c and HMGCR expression and fatty acid β-oxidation by up-regulating PPARα, CPT1A, and UCP2 expression. In addition, the S. aethiopicum L. peel extract might also improve oxidative stress by reducing endoplasmic reticulum stress and regulating the Nrf2 and Nf-κB molecular pathways. Altogether, these results demonstrated for the first time the possible application of the Lucanian S. aethiopicum peel extract for preventing obesity and managing NAFLD.