Due to their low binding affinities, detecting small-molecule fragments bound to protein structures from crystallographic datasets has been a challenge. Here, we report a trove of 65 new fragment hits for PTP1B, an “undruggable” therapeutic target enzyme for diabetes and cancer. These structures were obtained from computational analysis of data from a large crystallographic screen, demonstrating the power of this approach to elucidate many (∼50% more) “hidden” ligand-bound states of proteins. Our new structures include a fragment hit found in a novel binding site in PTP1B with a unique location relative to the active site, one that links adjacent allosteric sites, and, perhaps most strikingly, a fragment that induces long-range allosteric protein conformational responses. Altogether, our research highlights the utility of computational analysis of crystallographic data, makes publicly available dozens of new ligand-bound structures of a high-value drug target, and identifies novel aspects of ligandability and allostery in PTP1B. Display omitted •Computational reanalysis of a crystallographic small-molecule fragment screen for PTP1B•Identification of 65 new fragment hits across 59 new liganded crystal structures•New fragments reveal novel aspects of ligandability and allostery in PTP1B Mehlman et al. report 65 new small-molecule fragment hits for PTP1B, an “undruggable” therapeutic target enzyme for diabetes and cancer. These structures were obtained from computational reanalysis of data from a large crystallographic screen, demonstrating the power of this approach to elucidate many (∼50% more) “hidden” ligand-bound states of proteins.