Silybum marianum (L.) Gaertn, commonly known as milk thistle, is an herbal medicine rich in silymarin, a bioflavonoid complex. Historically, silymarin was used for treating liver diseases, but recent studies highlight silymarin’s potential for obesity management. This narrative review aims to provide an in-depth examination of the existing knowledge of Silybum marianum (L.) and its secondary compounds concerning obesity and associated comorbidities, summarizing data from in vitro, preclinical, and clinical studies. Obesity is a significant public health issue, exacerbated during the COVID-19 pandemic, as a major risk factor for mortality. It contributes to metabolic dysfunction, including oxidative stress, metainflammation, cardiovascular diseases, and type 2 diabetes development. Silymarin has demonstrated benefits on insulin signaling and lipid metabolism, as well as antioxidant and anti-inflammatory properties at the molecular level. Innovative studies also suggest silymarin’s potential as a prebiotic, positively influencing gut microbiota composition, a key factor affected by obesity. These promising findings support the potential anti-obesity action of silymarin in clinical practice. Looking forward, using silymarin as an innovative complementary therapy could offer substantial benefits for natural health promotion and obesity management. Nevertheless, further research into optimal doses and cellular mechanisms is still needed.