Despite decades of efforts, an urgent need remains to develop tumor cell-selective Ras-targeting therapies that can treat patients with Ras-driven tumors. Here we report modular engineered proteins that degrade Ras selectively in tumor cells that overexpress the tumor cell marker epithelial cell adhesion molecule (EpCAM) by fusing the Ras degrader Ras-Rap1-specific endopeptidase (RRSP) with the translocation domain of the Pseudomonas aeruginosa exotoxin A (ETA) or diphtheria toxin (DT). Redirection to EpCAM is achieved by a designed ankyrin repeat protein (DARPin). In 2D tumor cell cultures, complete degradation of Ras proteins after 24 hours was observed with EpCAM-targeted Ras degraders fused to ETA or DT in EpCAM-overexpressing MCF7 and HCT116 cells, with IC50 values at subnanomolar levels. The viability of EpCAM-low non-cancerous fibroblasts remained unaffected. In a 3D tumor-on-a-chip system, which mimics the natural tumor microenvironment, effective Ras degradation and selective toxicity towards tumor cells, particularly with the ETA-fused constructs, was determined on-chip. To conclude, we demonstrate the potential of modular engineered proteins to kill tumor cells highly selectively by simultaneously exploiting EpCAM as a tumor-specific cell surface molecule as well as Ras as an intracellular oncotarget in a 3D system mimicking the natural tumor microenvironment.