Background <p>Complement component 3 (C3) is increasingly recognized for its role in neurodegenerative processes; however, its specific impact on age-related hippocampal dysfunction remains poorly understood. This study investigates the effects of inducible C3 knockdown in adulthood on hippocampal function using a novel mouse model.</p> Methods <p>We developed a chimeric floxed C3 mouse line (<i>C3</i>^<i>fl/fl</i>) and crossed it with <i>Rosa-26-Cre-ERT2</i> ± mice, resulting in <i>C3</i>^<i>fl/fl</i>; <i>Rosa-26-Cre-ERT2</i>^± (<i>C3</i>iKO) mice that allow for global <i>C3</i> knockdown via Tamoxifen (TAM) administration at any age. Young adult female and male C3iKO mice were treated with TAM or corn oil (CO) as a control, to induce global C3 lowering in 4 cohorts of mice. Serum C3 levels were monitored throughout the lifespan for all cohorts. Other outcome measures varied by cohort and included behavior, longitudinal C3 levels in serum, C3 mRNA and protein levels in brain, C1q levels, immune gene expression in brain, gliosis, synaptic changes in hippocampus.</p> Results <p>TAM treatment led to a sustained reduction in C3 levels in serum, liver, and brain tissues of <i>C3</i>iKO mice. Global C3 lowering was associated with reduced expression of <i>C1q, C4b, IFNa</i><i>, </i><i>IFNb,</i> and increase expression of homeostatic genes <i>Tgfb1</i> and <i>Tgfbr1</i> in mouse brain one-year following TAM treatment. Notably, C3 lowering in adulthood conferred significant neuroprotection against age-related cognitive decline, which corresponded to preservation of hippocampal synapses and dendritic spine formation. Moreover, hippocampal long-term potentiation (LTP) impairments induced by Aβ-oligomers were rescued following <i>C3</i> knockdown, highlighting potential therapeutic implications.</p> Conclusions <p>Our C3iKO mouse model was consistently effective in lowering C3 levels in the brain and periphery in mice. The findings reported here demonstrate that global C3 lowering in adulthood, after brain development, protected the brain against age-associated hippocampal dysfunction and cognitive decline, suggesting that complement modulation may provide a neuroprotective strategy against brain aging. The <i>C3iKO</i> model provides a valuable platform for understanding the role of complement C3 in age-related neurodegenerative conditions, including Alzheimer’s disease. Further studies are needed to better understand these neuroprotective effects in models of neurodegeneration and to assess the therapeutic potential of complement modulation in the brain.</p>