Sorting Nexin 27 (SNX27) is a brain-enriched endosome-associated cargo adaptor crucial for cognitive and reward processing and implicated in various neurological conditions. However, its precise role in the nervous system remains elusive. We conducted comprehensive behavioral characterization of SNX27+/- mice, as the KO is not viable, covering motor, cognitive, and emotional aspects. Leveraging recent insights into SNX27's involvement in cellular stress signaling, we also investigated SNX27-stress interplay using a Caenorhabditis elegans Δsnx-27 mutant and wild-type rodents submitted to stress exposure. SNX27+/- mice and C. elegans Δsnx-27 mutants exhibited learning impairments, suggesting a conserved role for SNX27 on cognitive modulation across species. Notably, SNX27 downmodulation induced anxiety-like behavior in mice and associated with increased dendritic complexity in stress-responsive brain regions. Furthermore, we uncovered a direct link between SNX27 dysfunction and stress susceptibility in C. elegans and found that stress-exposed rodents displayed decreased SNX27 levels in stress-susceptible brain areas. In neuronal cultures, chronic pharmacological modulations that mimic stress-induced proteostasis dysfunction also significantly alter SNX27 levels, highlighting unexplored roles of SNX27 in the stress response. These findings underscore SNX27's relevance in cognition and anxiety regulation, shedding light on its impact on neuronal structure in stress-associated brain regions. Overall, our study unveils the evolutionary conservation of SNX27's role in cognition and provides novel insights into its involvement in anxiety-related behaviors and stress susceptibility, underscoring its significance in neurobiology.