Allium species and their organosulfur-derived compounds could prevent obesity and metabolic dysfunction, as they exhibit immunomodulatory and antimicrobial properties. Here, we report the anti-obesogenic potential and dose-dependent effects (0.1 or 1 mg/kg/day) of propyl propane thiosulfinate (PTS) in a murine model of diet-induced obesity. The obesogenic diet increased body weight gain and adipocyte size, and boosted inflammatory marker (Cd11c) expression in the adipose tissue. Conversely, PTS prevented these effects in a dose-dependent manner. Moreover, the higher dose of PTS improved glucose and hepatic homeostasis, modulated lipid metabolism, and raised markers of the thermogenic capacity of brown adipose tissue. In the colon, the obesogenic diet reduced IL-22 levels and increased gut barrier function markers (Cldn3, Muc2, Reg3g, DefaA); however, the highest PTS dose normalized all of these markers to the levels of mice fed a standard diet. Gut microbiota analyses revealed no differences in diversity indexes and only minor taxonomic changes, such as an increase in butyrate producers, Intestimonas and Alistipes, and a decrease in Bifidobacterium in mice receiving the highest PTS dose. In summary, our study provides preclinical evidence for the protective effects of PTS against obesity, which if confirmed in humans, might provide a novel plant-based dietary product to counteract this condition.