Protein tyrosine phosphatases (PTPs) regulate cell signaling pathways implicated in cancers, diabetes, immune diseases, and neurological diseases. Although PTPs are drug targets, inhibitor development has been limited by the low selectivity caused by the shallow PTP active site pocket with a conserved motif. Recent studies on PTP inhibitors have highlighted allosteric inhibition to circumvent these difficulties. PTPσ is a receptor-type PTP with phosphatase activity in the cytoplasmic region. PTPσ plays a critical role in neural development and hematopoietic stem cell regeneration and have been regarded as a drug target. We determined the crystal structure of the PTPσ complexed with its allosteric inhibitor Allo1. The structure showed an inhibitor-binding near the WPD loop, restricting the loop conformation switch during the catalysis. The allosteric binding site was further confirmed through mutagenesis and in vitro enzyme assays. The structural information can be exploited for the development of potent inhibitors.