Paraoxonase‐1 (PON1) has essential roles such as protecting low‐density lipoprotein against detoxification and oxidation of highly toxic compounds. Quinones are a class of compounds and a type of plant‐derived secondary metabolites. Here, PON1 was purified using very simple methods and evaluation of the interactions between the enzyme and some quinones. It was found that these quinones displayed effective inhibitor properties for PON1 with the IC50 values in the range of 3.27–82.90 μM and the K i values in the range of 2.50 ± 0.65 to 30.90 ± 7.20 μM. These quinones displayed distinct inhibition mechanisms. It was determined that except for 5‐hydroxy‐2‐methyl‐1,4‐naphthoquinone and 2‐methyl‐1,4‐naphthoquinone all quinones exhibit competitive inhibition effects. Also, molecular docking and in silico ADME studies were performed. Usage of drugs including quinone derivatives in structure with biological activity would be hazardous in some cases.