This study emphasizes to investigate the modulatory activity of trans-ferulic acid (TFA) on anti-inflammatory activity of etoricoxib (ETO) and underlying mechanisms via formalin-induced licking and paw edema model and in silico study. Inflammation was induced by injecting formalin (50 µL) into the right hind paw of mice. The animals were treated with different doses of TFA (25, 50, and 75 mg/kg, p.o.). The vehicle and ETO (35 mg/kg, p.o.) were provided as positive and negative control, respectively. ETO also served combined with TFA to evaluate the modulatory activity. The licking behavior was counted for the early and late phases, whereas the paw edema diameter was measured by using a slide caliper. All treatment was continued for 7 days until the edema was totally minimized to determine the inflammation's recovery capability for a specific group. Different computed and web tools were used to estimate molecular binding affinity, binding interactions, and pharmacokinetics. The findings demonstrated that TFA significantly (p <
0.05) enhanced the onset of licking and reduced the number of licks compared to vehicle group. TFA also showed a significant (p <
0.05) diminished in paw edema and complete recovered of the edema after 5 days of treatment indicating the anti-inflammatory effects. However, TFA with ETO notably diminished the anti-inflammatory effects of ETO by enhancing paw edema diameter and licking number. TFA also expressed elevated binding affinity of -7.5 and -6.5 kcal/mol toward nitric oxide (NO) synthase and COX-1, respectively. In conclusion, TFA exerted anti-inflammatory effects and reduces anti-inflammatory capability of ETO.