One thousand and four hundred crude organic extracts from natural plants, botanical chemicals were evaluated for anti‐inflammatory activity LPS treated cell lines: BV‐2 microligal cells, RAW 264.7 macrophages and C6 glioma cells. LPS is commonly used to invoke in vitro inflammation. However, studies using immortalized macrophages, microglia or astrocytoma (malignant phenotype) could result in an interfering variable when evaluating natural products which are both anti‐inflammatory and anti‐cancer (pro‐apoptotic) at similar/close concentrations. In this study, a high throuput HTP study was conducted on inflammatory parameters using an in vitro therapeutic index (iTI) = ratio of toxicity (LC50) / anti‐inflammatory potency (IC50) compared to reference controls (e.g. hydrocortisone, dexamethasone, iNOS inhibitor N6‐(1‐iminoethyl)‐L‐lysine (L‐NIL) and other OTC NSAIDs). Preliminary profiling studies showed (1) LPS activation of BV2 cells resulted > 10‐fold rise in IL‐6, MIP‐2, MIP‐1g, RANTES and nitric oxide (NO); (2) LPS activated RAW 264.7 cells generated > 10‐fold rise in sTNFR2, MCP‐1, IL‐6, GCSF, RANTES and NO (3) LPS/IFN‐g activated C6 glioma initiated >10‐fold rise in MCP‐1, CINC1, CINC2a, CINC3 and NO. Using NO2‐ production as a guideline molecule for HTP screening, the data show that of all compounds tested : the highest anti‐inflammatory differential LC50/IC50s (Ti ) with efficacy < 250μg/mL occurred in the presence of Ashwaganda, Elecampane, Feverfew, Tansy, Turmeric, Bayleaf, Rosemary, Green Tea, Yerba Santa and Centipeda Herb. Likewise, naturally derived substances with the highest anti‐inflammatory differential LC50/IC50s (Ti ) were established for cardamonin and to a lesser extent: butein, apigenin, EGCG, curcumin and quercetin. These substances had capacity to reduce NO, downregulate iNOS protein expression, significantly attenuate IL‐6 in activated RAW/BV2 cells and reduce levels of cytokine‐induced neutrophil chemoattractant CINC‐1/3, in C6 cells. These particular natural substances seem to hold therapeutic value above many others tested, with possible applications for future prevention of neuro inflammatory conditions / treatment of general inflammatory chronic disorders and possibly drug development for strategies to prevent multi‐organ damages associated with endotoxic shock.Support or Funding InformationNIMHD Grants G12MD007582 and Grant Number 1P20 MD006738