This project investigated the molecular mechanism by which *Platycodi Radix* extract (PRE; the ethanol extract of the root of *Platycodon grandiflorum*) prevents non-alcoholic fatty liver disease (NAFLD) in a high-fat diet (HFD)-induced fatty liver mouse model, using a liver-tissue shotgun proteomic and bioinformatic approach. Five-week-old male C57BL/6J mice were acclimatized and then maintained for 12 weeks on one of three diets: a normal chow diet (NCD), a high-fat diet (HFD), or an HFD supplemented with 5% (w/w) PRE. PRE supplementation prevented HFD-induced body-weight gain, fat accumulation, and hepatic steatosis, and improved glucose tolerance and serum lipid profiles. To elucidate the underlying mechanism, liver proteomes of the NCD, HFD, and PRE groups were profiled by LC-MS/MS (n = 3 per group), and proteins differing in relative abundance between NCD vs HFD and HFD vs PRE were interpreted by Ingenuity Pathway Analysis. This LC-MS/MS dataset was designed as a discovery-stage, exploratory screen for hypothesis generation rather than as standalone quantitative proof of differential expression; the resulting candidate proteins and pathways (notably decreased FXR/RXR-activation proteins and increased cholesterol-biosynthesis proteins, predicting enhanced bile-acid synthesis) were subsequently validated by targeted Western blotting and biochemical bile-acid measurement, on which the mechanistic conclusions of the study are based. This dataset comprises the liver-tissue LC-MS/MS data and the protein identification/quantification results supporting the conclusion that PRE prevents hepatic steatosis through modulation of FXR/RXR activation, cholesterol biosynthesis, and bile-acid synthesis pathways.