Purpose of Review <p>Neuroinflammation plays a pivotal role in disrupting synaptic resilience, thereby contributing to the onset and progression of major neurodegenerative and neuropsychiatric disorders. While its molecular mechanisms are well documented, the translational pharmacology linking these immune processes to synaptic recovery remains insufficiently synthesized. This review proposes an integrative framework of translational neuroimmune-synaptology, focusing on how modulation of glial activation, cytokine signaling, oxidative stress, and complement cascades can be strategically leveraged for Restoration of synaptic resilience.</p> Recent Findings <p>Recent primary studies demonstrate that selective microglial and astrocytic modulators, cytokine-targeted biologics, and mitochondrial protectants can reverse inflammation-driven synaptic loss. Nevertheless, clinical translation remains limited by barriers such as inadequate blood–brain barrier (BBB) penetration, off-target immune suppression, and inconsistent biomarker validation. Novel modalities—such as RNA therapeutics, CRISPR-based gene modulation, and AI-assisted drug repurposing—show potential to overcome these translational bottlenecks, provided their safety, delivery, and regulatory challenges are critically addressed. By reframing neuroinflammation as a modifiable and measurable determinant of synaptic function, this review consolidates mechanistic and pharmacological perspectives on neuroinflammation-induced synaptic dysfunction. Within the framework of translational neuroimmune-synaptology, it delineates actionable strategies to restore synaptic resilience and bridges preclinical discoveries with clinical therapeutic translation.</p>