Bacterial regulatory small RNAs (sRNAs) control gene expression by modulating transcription, translation and transcript degradation. A common silencing mechanism involves base-pairing at the ribosome-binding site to block ribosome recruitment and repress translation. Many sRNAs additionally recruit ribonucleases to accelerate target degradation and enhance silencing. Some also bind within coding sequences and function primarily through ribonuclease recruitment. Antisense oligonucleotides (ASOs) are short synthetic sequences designed to bind RNA. In bacteria, ASOs have been used to mimic sRNA-mediated repression by blocking ribosome binding and are therefore termed “blockmers”. We reasoned that bacterial ASOs capable of recruiting ribonucleases could enable more versatile gene silencing. Guided by our profiling of sRNA–mRNA pairs associated with RNase E, an endoribonuclease responsible for bulk RNA turnover in Escherichia coli, we systematically evaluated whether features of native sRNA-mediated regulation could be adapted to synthetic ASOs. ASO chemistry strongly influenced RNase E activity. Peptide nucleic acid, a widely used antibacterial ASO chemistry, did not support guided cleavage and instead inhibited RNase E activity on the target RNA. In contrast, selected modified ASOs directed sequence-specific RNase E cleavage in vitro. Following intracellular delivery, a lead ASO targeting the essential acpP transcript reduced target expression in bacterial cells, consistent with enhanced RNA degradation in vivo. We term these RNase-guiding ASOs “clipmers” for their ability to direct RNA cleavage. By coupling programmable sequence recognition to endogenous RNA decay, clipmers add a new mechanism to the antibacterial ASO toolkit. Because their activity does not depend solely on blocking translation initiation, clipmers may expand the targetable sequence space to coding regions, non-coding RNAs and structural RNAs.