Background: Obesity and aging are associated with the progressive loss of brown adipose tissue (BAT), an increase in visceral white adipose tissue (vWAT), and a reduction in subcutaneous white adipose tissue (sWAT). The progressive expansion of visceral obesity promotes a low grade of systemic chronic inflammation (meta-inflammation), contributing to the onset of comorbidities such as type 2 diabetes mellitus (T2DM), metabolic syndrome, and even cancer. Thus, preserving the thermogenic activity of adipose tissue and improving the metabolic flexibility of sWAT could be an effective strategy to prevent the development of metabolic chronic diseases and promote healthy aging. Precision nutrition has emerged as a complementary approach to control the metabolic alterations associated with unhealthy obesity and aging. In a previous work, we described that a silymarin-enriched extract from milk thistle (Mthistle) increased markers of browning and thermogenesis in vitro in human differentiated adipocytes (SGBS). Objectives/Methods: Therefore, this study aims to evaluate the potential of Mthistle to activate thermogenesis in a preclinical model of high-fat diet (HFD)-induced obesity (DIO). Results: Our results demonstrate that Mthistle increases systemic energy expenditure (EE), preserves body temperature after cold exposure, improves insulin resistance, and reduces inflammatory markers in WAT. Conclusions: Based on these results, silymarin-enriched extract from Mthistle may be proposed as a nutraceutical for the management of metabolic chronic diseases and/or accelerated aging.