Microglial-mediated neuroinflammation significantly impacts cognitive impairment, and modulating neuroinflammatory responses has emerged as a promising target for treatment. However, the specific role of microglial-mediated neuroinflammation in cognitive impairment associated with Alzheimer's disease (AD) remains unclear. In our continuous endeavors to seek potent anti-Alzheimer's agents, we recently synthesized and developed a series of peptidomimetic compounds, including dipeptide-68 bis-cyclohexylpropyl histidinamide (DBCH), derived from a caryopsis-1 peptide that has demonstrated anti-inflammatory and anti-microbial properties in various infectious diseases. Among the bioactive peptides synthesized, DBCH exhibited good neuroprotective and anti-inflammatory activity and high potency. Therefore, in this study, the neuroprotective and anti-inflammatory effects of DBCH were assessed in lipopolysaccharide (LPS)-stimulated BV-2 microglial cells and a scopolamine-induced C57BL/6 N amnesic mouse model. In the in vitro study, DBCH effectively suppressed the production and expression of nitric oxide (NO) and proinflammatory cytokines in BV-2 microglial cells stimulated with LPS. Furthermore, it effectively inhibited the LPS-triggered phosphorylation and activation of NF-κB/MAPK signaling and modulated inflammatory mediators, including iNOS and COX-2, in BV-2 microglial cells. In vivo results showed that DBCH administration of 5 or 10 mg/kg improved spatial memory learning and cognitive function in scopolamine-induced amnesic mice. Furthermore, DBCH treatment upregulated phosphorylated cAMP-response element-binding protein (p-CREB) and brain-derived neurotrophic factor (BDNF) levels and downregulated the inflammatory response. Overall, DBCH effectively prevented both scopolamine-induced cognitive impairment and neuroinflammation. Our research findings suggest that DBCH may serve as a medication for cognitive decline associated with AD.