This study aims to broadly evaluate the inhibitory efficiency of various ligands against the protein tyrosine phosphatase 1B (PTP1B) through molecular docking, PubChem database, and ADMET predictions. Initially, a redocking process was conducted to validate the docking protocol, yielding a root-mean-square deviation of 0.251 Å, indicating a reliable docking process. Sixty-seven ligands from the PubChem database that have similar molecular structures with co-crystal ligand 4-bromo-3-(carboxymethoxy)-5-[3-(cyclohexylamino)phenyl]thiophene-2-carboxylic acid, that has high binding energy with PTP1B were docked into the active site of the target protein, with binding energies compared to the known inhibitor MSI-1436. Twelve ligands with binding energies ranging from −8.5 to −8.2 kcal/mol were selected for further ADMET prediction using the pkCSM online tool. ADMET analysis revealed that the selected ligands exhibited good pharmacokinetic properties, including high water solubility, good Caco-2 permeability, and excellent human intestinal absorption. The distribution analysis indicated that the ligands predominantly remain in plasma rather than tissues, with medium blood-brain barrier permeability. Metabolism studies showed that while none of the ligands were substrates or inhibitors of CYP2D6, they were substrates of CYP3A4, except for one ligand. Excretion analysis suggested efficient elimination, with one ligand demonstrating the highest excretion speed. Toxicity screening using AMES, liver, and skin toxicity assays identified four potential therapeutic compounds (41821587, 25507970, 17528575, 101128457) that exhibited no AMES toxicity, hepatotoxicity, or skin sensitization. The study further analyzed and presented the interactions of these four ligands with the target protein. The comprehensive evaluation of docking, pharmacokinetic, and toxicity properties underscores the potential of these compounds as therapeutic inhibitors of PTP1B, paving the way for future experimental validations.