Pathogens such asPseudomonas aeruginosaadvantageously modify animal host physiology, for example, by inhibiting host protein synthesis. Translational inhibition of insects and mammalian hosts byP.aeruginosautilizes the well-known exotoxin A effector. However, for the infection ofCaenorhabditis elegansbyP.aeruginosa, the precise pathways and mechanism(s) of translational inhibition are not well understood. We found that upon exposure toP.aeruginosaPA14,C.elegansundergoes a rapid loss of intact ribosomes accompanied by the accumulation of ribosomes cleaved at helix 69 (H69) of the 26S ribosomal RNA (rRNA), a key part of ribosome decoding center. H69 cleavage is elicited by certain virulentP.aeruginosaisolates in a quorum sensing (QS)–dependent manner and independently of exotoxin A–mediated translational repression. H69 cleavage is antagonized by the 3 major host defense pathways defined by thepmk-1,fshr-1, andzip-2genes. The level of H69 cleavage increases with the bacterial exposure time, and it is predominantly localized in the worm’s intestinal tissue. Genetic and genomic analysis suggests that H69 cleavage leads to the activation of the worm’szip-2-mediated defense response pathway, consistent with translational inhibition. Taken together, our observations suggest thatP.aeruginosadeploys a virulence mechanism to induce ribosome degradation and H69 cleavage of host ribosomes. In this manner,P.aeruginosawould impair host translation and block antibacterial responses.