Many recurrent tumors are caused by small subset of aggressive cancer cells called cancer stem cells (CSCs). Because CSCs self-renew and cause metastasis, traditional chemotherapy treatments often miss them, causing cancer relapse due to CSC drug resistance. H358 is a non-small cell lung cancer (NSCLC) cell line that contains CSCs with the seldom-explored cell surface protein plectin, which is associated with poor cancer prognosis. Plectin can be selectively targeted since it migrates to the surface of CSCs but remains in the cytosol of normal cells, thus allowing treatment of the root cause without significant side effects. In previous studies, the monomeric peptoid PCS2 was identified to effectively target this protein. We dimerized PCS2 to form twelve different homodimers with varying linker lengths and compositions, with hopes that the “avidity effect” would result in improved plectin targeting. In this study, we used a 5-day cytotoxicity (MTS) assay with various compound concentrations to compare the effect of the parent dimer PCS2D1.2 to that of its eleven linker variations on the viability of H358 cells. As we studied linker lengths that ranged from two to eighty-five atoms in hopes of finding some correlation between the linker length and peptoid activity, we found that PCS2D1.2’s linker length of four carbon atoms allowed it to show optimal activity, while the modified compounds with shorter or longer linkers had incrementally weaker effects on cancer cells. This linker length optimization was combined with other in vitro and in vivo studies, all of which confirmed that PCS2D1.2 was indeed the most effective out of the twelve compounds in targeting plectin in H358 CSCs. PCS2D1.2 is thus a selective and promising CSC drug-lead that could potentially be developed and used in combination with traditional chemotherapy drugs, which are known to typically rid the body of only non-CSCs.