Colorectal cancer (CRC) is the third leading cause of cancer-related death. Colorectal mucosa has high levels of oxidative stress (OS) landmarks. OS has deleterious effect on cell structures as lipids, proteins and DNA. Markers of protein oxidation are named as advanced oxidation protein products (AOPPs) which have been considered as novel disease biomarkers. OS may also induce DNA damage which leads to mutation of chromosomes. Paraoxonase 1 (PON1) and Arylesterase (ARE) metabolize different substrates and act as antioxidant enzymes. Disruption of epigenetic processes can lead to altered gene function and malignant transformation. Altered expression of genes that encode histone deacetylase (HDACs) are linked to tumor development. The aim of this study was to evaluate the PON1 and ARE activities in CRC patients and to assess the epigenetic fingerprint via estimation of HDAC. The study was carried out on 30 CRC patients. After excision of tumor, segments were divided into two groups: group A (Control group) included parts taken from safety margin; Group B: (CRC group) subdivided into 3 grades, grade I: well differentiated tumor, grade II: moderately differentiated tumor, and grade III: poor differentiated tumor. CRC groups showed elevation of OS landmarks (AOPPs and DNA damage), HDACs activity and significant decrease in the level of PON1 and activities of PON1 and ARE. The histopathological results were correlated with the laboratory results. It was concluded that the damage of AOPPs and DNA is novel biomarkers in diagnosis of CRC; PON1 is important protective antioxidant enzyme and HDAC activity estimation is a promising line in CRC diagnosis.