Receptor Protein Tyrosine Phosphatases (RPTPs) are one of the most important regulators of receptor tyrosine kinases (RTKs) and therefore play a crucial role in mammalian signal transduction. But our still‐incomplete understanding of the structural aspects of their regulation and the lack of selective agonists have hampered efforts to understand their roles in downstream signaling regulation, and to pursue them as potential therapeutic targets. However, the reported ability of RPTP homodimerization to antagonize their catalytic activity presents potential opportunities to develop unique strategies to modulate the activity of RPTPs.We recently reported (Block et al., JBC, 2019; doi:10.1074/jbc.RA119.010229) that the homodimerization of a representative member of the RPTP family (protein tyrosine phosphatase receptor J or PTPRJ; also known as DEP1) is regulated by specific transmembrane (TM) residues, and that these interactions are essential in regulating its enzymatic activity and substrate access in cells.Building on these new insights and in response to the lack of selective agonists, we present here the design and testing of a novel class of tumor‐selective peptide capable of binding to the TM domain of PTPRJ and disrupting its homodimerization. By doing so, it promotes PTPRJ TM‐mediated access to EGFR, reduces the phosphorylation of EGFR (a known substrate) and other downstream signaling effectors, and antagonizes EGFR‐driven cancer cell phenotypes.This class of peptide represents a novel allosteric and a possibly orthogonal way to target the activity of PTPRJ and RTKs phosphorylation. It could therefore be used not only as probes to tease out PTPRJ regulating mechanisms but also for therapeutic purposes via the attenuation of signaling by dysregulated RTKs.