Eight new amide‐based carboxylate derivatives were synthesized and evaluated for anti‐inflammatory potentials using in‐vitro, in‐vivo and in silico studies. In cyclooxygenase‐2 assay, maximum percent antagonist potential was exhibited by sodium 4‐((4‐fluorophenyl) amino)‐4‐oxobutanoate (93.91 %), bis ((4‐((4‐methoxy‐2‐nitrophenyl)amino)‐4‐oxobutanoyl)oxy) zinc (93.04 %), and bis ((4‐((4‐bromo‐2‐fluorophenyl) amino)‐4‐oxobutanoyl)oxy)zincio (2‐bromopyridine) (92.64 %) with IC50 values of 1.65, 2.08, and 0.288 μM/ml respectively. Celecoxib demonstrated 98.60 % effect with an IC50 value of 0.041 μM/ml. In LOX assay, 4‐((4‐methoxy‐2‐nitrophenyl)amino)‐4‐oxobutanoic acid (97.03 %), bis ((4‐((4‐methoxy‐2‐nitrophenyl)amino)‐4‐oxobutanoyl)oxy)zinc (95.45 %), and (92.53 %) demonstrated maximum percent effect with IC50 values 3.48, 0.45, and 0.83 μM/ml respectively. The standard 5‐lipoxygenase inhibitor (montelukast) resulted from a 98.39 % inhibitory effect with an IC50 value of 0.194 μM/ml. In in‐vivo analysis, the potent tested compounds (5, 10, and, 20 mg/kg) significantly (p<0.001) reversed the induced edema by carrageenan. The standard drug aspirin displayed significant results (74–83 %). The standard drugs in these phlogestic agents displayed excellent results like cetirizine (67.9 %), celecoxib (81.61 %), icatibant (82.22 %) and nemesulide (87.17 %) at 5th h. The compounds displayed the inhibitory potential against targeted proteins. 4‐((4‐methoxy‐2‐nitrophenyl)amino)‐4‐oxobutanoic acid, 4‐((4‐fluorophenyl)amino)‐4‐oxobutanoic acid and sodium 4‐((4‐bromo‐2‐fluorophenyl)amino)‐4‐oxobutanoate shown excellent behavior by giving negative binding energies close of standard drugs montelukast (5F1A: −7.9 kcal/mol) and diclofenac (3O8Y: −8.5 Kcal/mol). The tested compounds were proven significant anti‐inflammatory potentials.