E‐cadherin is an essential adhesion protein as well as a tumor suppressor that is silenced in many cancers. Its adhesion‐dependent regulation of signaling has not been elucidated. We report that E‐cadherin can negatively regulate, in an adhesion‐dependent manner, the ligand‐dependent activation of divergent classes of receptor tyrosine kinases (RTKs), by inhibiting their ligand‐dependent activation in association with decreases in receptor mobility and in ligand‐binding affinity. E‐cadherin did not regulate a constitutively active mutant RTK (Neu^*) or the ligand‐dependent activation of LPA receptors or muscarinic receptors, which are two classes of G protein‐coupled receptors. EGFR regulation by E‐cadherin was associated with complex formation between EGFR and E‐cadherin that depended on the extracellular domain of E‐cadherin but was independent of β‐catenin binding or p120‐catenin binding. Transfection of E‐cadherin conferred negative RTK regulation to human melanoma and breast cancer lines with downregulated endogenous E‐cadherin. Abrogation of E‐cadherin regulation may contribute to the frequent ligand‐dependent activation of RTK in tumors.