This study explores the effects of a nutraceutical blend with prebiotics, β-glucans, essential minerals, and silymarin on gut microbiota, inflammation, and sleep quality in obesity through microbiota reshaping and metabolic improvements over 90 days. A double-blind, randomized trial was conducted on 77 participants divided into two groups receiving either a standard nutraceutical blend (NSupple) or a silymarin-enriched blend (NSupple_Silybum). Fecal and plasma samples were collected at baseline and post-supplementation for gut microbiota, metabolic, and inflammatory marker analysis. The results showed a reduction in body weight, waist-to-height ratio, total cholesterol, and fractions in the NSupple_Silybum group. There was a dysbiosis recovery shown by the increase in beneficial gut bacteria, such as Lentisphaerae phylum, Lactobacillus and Faecalibacterium genera, and Faecalibacterium prausnitzii in the NSupple group, with a concurrent reduction in Adlercreutzia and Sutterella in the NSupple_Silybum group. Both groups demonstrated improved inflammatory profiles by the reduced TNF-α/IL-10 ratio, reduced cortisol levels, and reduced Firmicutes/Bacteroides ratio. Additionally, improvements in sleep quality were associated with reductions in pro-inflammatory cytokines and improved microbiota composition. The nutraceutical blend reshaped gut microbiota, enhanced anti-inflammatory species, and improved metabolic and sleep parameters, highlighting its potential as a nutritional strategy for managing obesity and reducing inflammation.