Receptor tyrosine kinases (RTK) have been the most prevalent therapeutic targets in anti-cancer drug development. However, the emergence of drug resistance toward single target RTK inhibitors remains a major challenge to achieve long-term remissions. Development of alternative RTK inhibitory strategies that bypass drug resistance is much wanted. In the present study, we found that selected cell surface RTKs were inhibited and crosslinked into detergent resistant complexes by oligomeric but not monomeric concanavalin A (ConA). The inhibition of RTKs by ConA led to suppression of pro-survival pathways and induction of apoptosis in multiple cancer cell lines, while overexpression of constitutively activated protein kinase B (AKT) reversed the apoptotic effect. However, major cell stress sensing checkpoints were not influenced by ConA. To our knowledge, selective crosslinking and inhibition of cell surface receptors by ConA-like molecules might represent a previously unidentified mechanism that could be potentially exploited for therapeutic development.