Abstract(3‐(4‐Fluorophenyl)oxyran‐2‐yl)(naphthalene‐2‐yl)methanone 2 was prepared from the reaction of 3‐(4‐fluorophenyl)‐1‐(naphthalen‐2‐yl)prop‐2‐en‐1‐one (1) with hydrogen peroxide and reacted with different nucleophiles such as hydrazine hydrate, phenyl hydrazine, thiosemicarbazide to give 4‐hydroxy‐1H‐pyrazole derivatives 3a,b‐4. Also, compound 2 was treated with hydroxylamine hydrochloride to give the substituted 2,3‐dihydroisoxazole 5. Similarly, compound 2 was treated with carbon disulfide, phenyl isothiocyanate, and phenyl isocyanate to give the corresponding compounds 6–8. Various spectroscopic techniques and elemental analysis were used to determine the molecular structures of the new derivatives. All the new analogs were screened against five human pathogenic microbial strains: Escherichia coli and Pseudomonas aeruginosa as Gram‐negative bacteria, Bacillus subtilis and Staphylococcus aureus as Gram‐positive bacteria and the yeast Candida albicans using agar diffusion method. Compound 4 exhibited moderate antimicrobial activity against all the tested microorganisms compared to positive control ciprofloxacin and fluconazole. On the other hand, the free radical scavenging activity of the new compounds using DPPH assay protocol revealed that most of the compounds have a weak reducing activity. Moreover, compounds 4 and 8 were docked against 1KZN protein (DNA gyrase), 3FYV and 5V5Z showing the ability to interact with key amino acid residues and the potential to act as inhibitors.