In search of new active molecules, a small focused library of the synthesis of 3‐(trifluoromethyl)‐1‐(perfluorophenyl)‐1H‐pyrazol‐5(4H)‐one derivatives (4a‐d, 5a‐f, and 6a‐e) has been efficiently prepared via the Knoevenagel condensation approach. All the derivatives were synthesized by conventional and nonconventional methods like ultrasonication and microwave irradiation, respectively. Several derivatives exhibited excellent anti‐inflammatory activity compared to the standard drug. Furthermore, the synthesized compounds were found to have potential antioxidant activity. In addition, to rationalize the observed biological activity data, an in silico absorption, distribution, metabolism, and excretion (ADME) prediction study also been carried out. The results of the in vitro and in silico studies suggest that the 3‐(trifluoromethyl)‐1‐(perfluorophenyl)‐1H‐pyrazol‐5(4H)‐one derivatives (4a‐d, 5a‐f, and 6a‐e) may possess the ideal structural requirements for the further development of novel therapeutic agents.