Trigonella foenum-graecum (fenugreek) is an important medicinal plant, well known for its antiinflammatory properties. However, the underlying cellular and molecular mechanisms of its action remain largely unknown. The apoptosis associated speck like protein containing a caspase recruitment domain (CARD) (ASC) is central to inflammatory and cell death pathways in innate and adaptive immunity. Here, we show that fenugreek seed extract provides cytoprotection to bacterial lipopolysaccharide (LPS) inflammed and nanosilica-treated fibroblasts via a reactive oxygen species independent pathway. All atom molecular dynamics simulations of ASC-ligand complex reveal that individual phytochemicals in fenugreek can bind to ASC via specific non-covalent interactions. These data show that a synergistic effect of fenugreek phytochemicals with the ASC protein alters its molecular properties resulting in altered cellular function. Such information is crucial to the development of targeted therapeutic interventions for inflammatory diseases. © 1996-2017.