AbstractCaenorhabditis elegans mutants deleted for TDP‐1, an ortholog of the neurodegeneration‐associated RNA‐binding protein TDP‐43, display only mild phenotypes. Nevertheless, transcriptome sequencing revealed that many RNAs were altered in accumulation and/or processing in the mutant. Analysis of these transcriptional abnormalities demonstrates that a primary function of TDP‐1 is to limit formation or stability of double‐stranded RNA. Specifically, we found that deletion of tdp‐1: (1) preferentially alters the accumulation of RNAs with inherent double‐stranded structure (dsRNA); (2) increases the accumulation of nuclear dsRNA foci; (3) enhances the frequency of adenosine‐to‐inosine RNA editing; and (4) dramatically increases the amount of transcripts immunoprecipitable with a dsRNA‐specific antibody, including intronic sequences, RNAs with antisense overlap to another transcript, and transposons. We also show that TDP‐43 knockdown in human cells results in accumulation of dsRNA, indicating that suppression of dsRNA is a conserved function of TDP‐43 in mammals. Altered accumulation of structured RNA may account for some of the previously described molecular phenotypes (e.g., altered splicing) resulting from reduction of TDP‐43 function.