In neurodegenerative diseases, such as Alzheimer’s disease, Huntington’s disease, Parkinson’s disease and multiple sclerosis, neuroinflammation induced by the microglial activation plays a crucial role. In effort to develop effective anti-neuroinflammatory compounds, different new linear polyoxygenated diarylheptanoids were synthesized. In LPS-triggered BV-2 microglial cells their ability to reduce the concentration of IL-6 and TNF-α pro-inflammatory cytokines was evaluated. Moreover, their effect on NF-κB and ATP citrate lyase (ACLY), a recently emerged target of metabolic reprogramming in inflammation, was assessed. Finally, we turned our attention to inflammatory mediators derived from the cleavage of citrate catalyzed by ACLY: prostaglandin E2, nitric oxide and reactive oxygen species. All compounds showed null or minimal cytotoxicity; most of them had a great anti-neuroinflammatory activity. Diarylheptanoids 6b and 6c, bearing a halide atom and benzyl ether protective groups, exhibited the best effect since they blocked the secretion of all inflammatory mediators analyzed and reduced NF-κB and ACLY protein levels. Display omitted •New linear polyoxygenated diarylheptanoids were synthesized by cross metathesis.•New diarylheptanoids reduce IL-6, TNF-α, PGE2, ROS and NO in LPS-induced microglia.•New diarylheptanoids inhibited NF-κB transcription factor and its target gene ACLY.•Diarylheptanoids 6b and 6c were the best in reducing microglial neuroinflammation.•Halide atom and benzyl ether strengthen anti-neuroinflammatory activity.