Poria cocos(PC) is a medicinal herb frequently used in weight-loss clinical trials, however the mechanisms by which its compounds target orexigenic receptors including the neuropeptide Y1receptor (Y1R) remain largely unknown. This study aimed to screen PC compounds for favourable pharmacokinetics profiles and examine their molecular mechanisms targeting Y1R. Forty-three PC compounds were systematically sought from pharmacological databases and docked with Y1R (PDB: 5ZBQ). By comparing the relative binding affinities, pharmacokinetics and toxicity profiles, we hypothesised that compounds designatedPC13,4-Dihydroxybenzoic acid,PC8Vanillic acid,PC401-(alpha-L-Ribofuranosyl)uracil, could be potential antagonists as they contact major residues Asn283 and Asp287, similar to various potent Y1R antagonists. In addition,PC21Poricoic acid B,PC22Poricoic acid G andPC4316alpha,25-Dihydroxy-24-methylene-3,4-secolanosta-4(28),7,9(11)-triene-3,21-dioic acid, contacting Asn299, Asp104 and Asp200 proximal to the extracellular surface could also interfere with agonist binding by stabilising the extracellular loop (ECL) 2 of Y1R in a closed position. Owing to their selective interaction with Phe302, an important residue in binding of selective Y1R antagonists,PC12beta-Amyrin acetate,PC263-Epidehydrotumulosic acid andPC27Cerevisterol were proposed as putative antagonists. Following the consensus approach,PC12beta-Amyrin acetate,PC263-Epidehydrotumulosic acid andPC27Cerevisterol were identified as candidate compounds due to their high affinities (-12.2, -11.0 and -10.8 kcal, respectively), high drug-likeness and low toxicity profiles. Trajectory analyses and energy contributions ofPC12-Y1R complex further confirmed their structural stability and favourable binding free energies, highlighting the feasibility and possible development ofPC12beta-Amyrin acetate as a future Y1R inhibitor.