Interleukin-1β (IL-1β) is mainly produced by macrophages through NLRP3 (NOD-, LRR- and pyrin domain-containing protein 3) inflammasome, which is considered as the culprit of the inflammatory crosstalk between macrophages and adipocytes. Ainsliadimer C (AC), a disesquiterpenoid isolated from Ainsliaea macrocephala, was found to dose-dependently suppress IL-1β secretion in lipopolysaccharide (LPS) plus ATP-treated THP-1 macrophages, through inhibiting the activation of NLRP3 inflammasome. AC activated the NAD⁺-dependent deacetylase Sirtuin-1 (SIRT1), resulting in reduced acetylation level of NLRP3. Molecular docking results suggested AC binds to the STAC-binding domain to increase the affinity of the substrate to the catalytic domain of SIRT1. In addition, AC attenuated the inflammatory response in 3T3-L1 adipocytes induced by macrophage-conditioned medium. In LPS-induced acute inflammatory mice, AC treatment suppressed the pro-inflammatory cytokine levels in serum and epididymal white adipose tissue (eWAT), and attenuated macrophage infiltration into eWAT, to mitigate adipose tissue inflammation. Taken together, AC represents a novel scaffold to ameliorate adipose tissue inflammation, which might be a candidate to treat obesity associated metabolic diseases.