Evolving evidence suggests that brain inflammation and the buildup of proinflammatory cytokines increases the risk for cognitive decline and cognitive dysfunction. Interleukin-1β (IL-1β), acting via poorly understood mechanisms, appears to be a key cytokine in causing these deleterious effects along with a presumably related loss of LTP-type synaptic plasticity. We hypothesized that IL-1β disrupts BDNF signaling cascades and thereby impairs the formation of filamentous actin (F-actin) in dendritic spines, an event that is essential for the stabilization of LTP. Actin polymerization in spines requires phosphorylation of the filament severing protein cofilin and is modulated by expression of the immediate early gene product Arc. Using rat organotypic hippocampal cultures, we found that IL-1β suppressed BDNF-dependent regulation of Arc and phosphorylation of cofilin and CREB, a transcription factor regulating Arc expression. IL-1β appears to act on BDNF signal transduction by impairing the phosphorylation of insulin receptor substrate 1 (IRS-1), a protein which couples activation of the BDNF receptor TrkB to downstream signaling pathways regulating CREB, Arc, and cofilin. IL-1β upregulated p38 MAPK, and inhibiting p38 MAPK prevented IL-1β from disrupting BDNF signaling. IL-1β also prevented the formation of F-actin in spines and impaired the consolidation, but not induction, of BDNF-dependent LTP in acute hippocampal slices. The suppressive effect of IL-1β on F-actin and LTP was prevented by inhibiting p38 MAPK. These findings define a new mechanism for the action of IL-1β on LTP and point to a potential therapeutic target to restore synaptic plasticity.