Neurodegenerative diseases encompass a broad range of disorders in which neurons are progressively lost, including amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). Although ALS and FTD possess distinct neuropathological features, almost all ALS cases and approximately half of FTD cases share a common molecular pathology: mislocalization and aggregation of the RNA-binding protein TDP-43. TDP-43 pathology also occurs in numerous other forms of neurodegeneration, making it a critical therapeutic target. Previous work has shown that RNA solubilizes TDP-43 in vitro and in cellular models, suggesting that RNA may be therapeutic for disorders with TDP-43 proteinopathy. Here, we set out to advance the potential of RNA chaperones for TDP-43. We utilize a variety of biochemical and biophysical techniques to understand the mechanism by which short RNA molecules chaperone TDP-43, finding that RNA binding stabilizes the structure of the RNA-recognition motifs of TDP-43 and allosterically destabilizes the structure of a region of the prion-like domain (PrLD). We next determine that RNA effectively chaperones diverse forms of TDP-43 found in disease. We identify numerous sequences derived from endogenous RNA interactors of TDP-43 that are potent chaperones, including an RNA chaperone that mitigates disease phenotypes in patient induced pluripotent stem cell-derived neurons and a mouse model of TDP-43 proteinopathy. We rationally design short RNA molecules to characterize the essential sequence features of effective RNA chaperones, finding that RNA sequence composition, patterning, and modification status each impact chaperone activity against both liquid and solid phases of TDP-43. We also characterize the aggregation of the splice isoform sTDP-43, finding that its aggregation is due to steric zipper sequences within a short, isoform-specific C-terminal region. We find that RNA chaperones sTDP-43 and that steric zippers promote sTDP-43 aggregation and mislocalization in neurons. The work presented here characterizes TDP-43 aggregation and provides strong support for the further development of RNA chaperones as therapeutic agents for neurodegenerative diseases characterized by TDP-43 proteinopathy.