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Peroxiredoxin 6 (PRDX6) is expressed throughout the brain, including the hippocampus, where it plays a potential role in synaptic regulation and forming emotional and spatial memories. PRDX6 is predominantly detected in the female mouse’s hippocampus; thus, we investigate the effect of the Prdx6 gene on behavioral phenotypes and synaptic functions using female Prdx6 knockout (Prdx6^−/−) mice. Our results demonstrate that female Prdx6^−/− mice exhibited anxiety-like behavior, enhanced contextual fear memory, and impaired spatial memory. We also found increased, paired–pulse facilitation ratios, and decreased long-term potentiation (LTP) in the hippocampal region of these female Prdx6^−/− mice. The present study helps to understand better the PRDX6’s role in emotional response and spatial memory formation in female mice.