The study aims to synthesize benzamide derivatives of p‐aminophenol (PAP) by reacting with 4‐benzoyl chloride. The reaction of PAP yields four derivatives: P‐1 [N‐(4‐hydroxyphenyl)benzamide], P‐2 [4ˊ‐bromo‐N‐(4‐hydroxyphenyl)benzamide], P‐3 [4ˊ‐nitro‐N‐(4‐hydroxyphenyl)benzamide] and P‐4 [3ˊ,5ˊ‐dintro‐N‐(4‐hydroxyphenyl)benzamide] and evaluation of biological activity. PAP derivatives hot plate analgesic test produced a significant analgesic effect. The higher analgesic activities were observed at 60 min for all derivatives P‐1, P‐2, P‐3, and P‐4 at 47.65, 48.13, 47.08, and 45.47%, respectively. Derivatives of PAP were also shown to have statistically significant (p < 0.001) analgesic efficacy in the writhing test. The maximum percent inhibition of the writhing by P‐2 (82.11%). In vivo anti‐inflammatory examination confirmed that P‐1, P‐2, and P‐4 prevented carrageenan‐induced rat paw edema for 60–240 min. The toxicity of PAP derivatives P‐1 and P‐4 was lower than paracetamol. Experiments demonstrate that derivatives exhibit less cytotoxicity. The compounds P‐3 and P‐4 inhibited egg and bovine albumin denaturation better at lower dosages in anti‐inflammatory experiments. Molecular docking and ADMET showed that derivatives might inhibit COX‐1 and COX‐2. Also, P‐4 demonstrated the highest binding affinity (−8.2 kcal/mol) for COX‐1 and P‐1 (−8.4 kcal/mol) for COX‐2. According to computational and experimental studies, PAP derivatives may inhibit cyclooxygenase to relieve pain, inflammation, and fever.