Ten novel usnic acid based imidazolium salts were synthesized by employing a two-step protocol. The anti-inflammatory potential of the newly synthesised compounds was evaluated in vitro against cytokine proteins TNF- α and IL-1 β secreted from U937 cells. Some of the imidazolium salts exhibited promising anti-inflammatory activity against the TNF-α and IL-1β with IC50 values ranging between 5.3 μM - 7.5 μM, which are many folds lower than that of the parent compound (>100 μM). Most significantly, substitution with electronegative groups in imidazolium salts of usnic acid found to be more potent and exhibiting enhanced anti-inflammatory activity