Innate Toll-like receptors (TLRs) play a critical role in activating microglia in various diseases of the CNS. Our study aimed to examine the widely unknown consequences of stimulation of TLR7/8, which are known to recognize single-stranded RNA (ssRNA), e.g. from viruses. For this, we conducted electrophysiological local field potential recordings of neuronal gamma-oscillations (30-70 Hz), biochemical assays, and immunofluorescence in rat organotypic hippocampal slice cultures. Our findings reveal that single exposure (48 h) to the TLR7/8 agonist Resiquimod (R848) induces the release of pro-inflammatory cytokines, like TNF-α, without disturbing neuronal network function. Paired exposure with lipopolysaccharide (LPS), a known TLR4 agonist, leads to a more pronounced, yet still moderate phenotype, characterized by the sporadic occurrence of neural bursts or oscillations in the beta frequency band (12-30 Hz). Paired exposure with interferon-gamma (IFN-γ) results in a severe phenotype characterized by loss of network function and neurodegeneration. Immunofluorescence analysis demonstrated that this neurodegeneration is accompanied by microglial proliferation. The central role of activated microglia in these detrimental processes was further substantiated by the successful prevention of neurodegeneration and recovery of network activity through microglial depletion using clodronate. Additionally, inhibiting the TLR7/8 pathway with Enpatoran (M5049) proved to be a second effective neuroprotective strategy. Our experimental outcomes describe potential implications of TLR7/8 stimulation in viral-associated brain disorders, as well as in other CNS diseases associated with neuroinflammation such as Alzheimer's disease and multiple sclerosis.