Background: Nrf2, a master regulator of antioxidant defenses, with its expression diminishing with age, disrupting redox homeostasis and increasing susceptibility to brain damage and neurodegenerative diseases such as Alzheimer’s. While Nrf2’s neuroprotective role is established, the early, region-specific effects of its loss—particularly in the hippocampus—are poorly understood. We investigated whether Nrf2 deficiency influences tau seeding and spreading in a paired helical filament (PHF)-tau inoculated mouse model, thereby shaping an accelerated aging molecular phenotype. Methodology: We evaluated the effects on tau seeding and spreading mechanisms using a “sporadic” tauopathy model in the Nrf2-KO background, assessing tau propagation after hippocampal inoculation with human AD-derived PHF-tau. To uncover the alterations underlying observed differences, we performed phosphoproteotranscriptomic analyses of hippocampal tissue from Nrf2-KO mice, followed by RT-qPCR and Western blot validation, and compared the results with those from WT mice. Results: PHF-tau inoculation at 3 months of age in Nrf2-KO mice exhibited markedly reduced tau seeding and spreading compared to WT after 3 months of incubation. Molecular characterization of the Nrf2-KO hippocampus was carried out applying multiomic approaches. Transcriptomic profiling revealed 745 deregulated transcripts in the Nrf2-KO mice, with immune/metabolic pathways upregulated and, surprisingly, oxidative stress/redox genes downregulated. RT-qPCR confirmed reduced expression of key antioxidant effectors and anti-inflammatory receptors, alongside altered astrocytic markers. Proteomics identified 157 proteins linked to mitochondrial, synaptic, and inflammatory processes, while phosphoproteomics revealed 824 dysregulated phosphosites enriched in synaptic and cytoskeletal networks. Western blot showed increased levels of GFAP-δ, AQP4, 8-OHdG, and MDAL and reduced Gstm2. In addition, total tau and 4R-tau showed decreased levels in Nrf2-KO animals, in contrast to 3R-tau that was increased. Conclusion: Nrf2 loss creates an immature-like hippocampal environment—characterized by suppressed antioxidant/anti-inflammatory defenses, astrocytic shifts, and altered tau isoform balance—that resists tau propagation at early age. This phenotype suggests Nrf2 regulates both redox homeostasis and, subsequently, the cellular maturity required for tau spread, highlighting potential therapeutic value in modulating host environment to slow tauopathy progression.