hnRNPK is a multifunctional protein that plays an important role in cancer cell proliferation and metastasis via its RNA- and DNA-binding properties. Previously we showed that cell-penetrating peptides derived from the RGG RNA-binding domain of SAFA (hnRNPU) disrupt cancer cell proliferation and survival. Here we explore the efficacy of a peptide derived from the RGG domain of hnRNPK. This peptide acts in a dominant-negative manner on several hnRNPK functions to induce death of multiple types of cancer cells. The peptide phenocopies the effect of hnRNPK knockdown on its mRNA-stability targets such as KLF4 and EGR1 and alters the levels and locations of long non-coding RNAs (lncRNAs) and proteins required for nuclear and paraspeckle formation and function. The RGG-derived peptide also decreases euchromatin as evidenced by loss of active marks and polymerase II occupancy. Our findings reveal the potential therapeutic utility of the hnRNPK RGG-derived peptide in a range of cancers.