Alcohol consumption is a risk factor associated with colorectal cancer (CRC); however, some studies have reported that moderate alcohol may not contribute additional risk for developing CRC while others suggest that moderate alcohol provides a protective effect that reduces CRC risk. The purpose of this study was to determine the effects of moderate alcohol (20% ethanol) administered on alternate days for 3 months in male Wistar rats on biomarkers that were associated with CRC development. Blood samples and colon mucosa samples were collected from the experimental alcohol group and the control group at the end of the study and were used to evaluate a variety of biomarkers that were associated with inflammation, DNA damage, antioxidant activity, and acetaldehyde clearance. The results revealed that moderate alcohol significantly decreased cyclooxygenease-2 (COX-2) expression, a marker for inflammation that is associated with CRC risk. Rats treated with moderate alcohol were also found to have significantly lower 8-oxo-dG levels, a marker of DNA damage, with no significant increase in repair activity by 8-oxoguanine DNA glycosylase 1 (OGG-1), a base excision repair enzyme responsible for removing 8-oxo-dG damage. The alcohol group had significantly increased glutathione-S-transferase M1 (GSTM1) expression, which is an antioxidant defense enzyme that helps detoxify carcinogens, like acetaldehyde, and also resulted in significantly increased aldehyde dehydrogenase 2 (ALDH2) expression, which allowed for greater acetaldehyde clearance. Increased expression of GSTM1 and ALDH2 likely contributed to reduce mucosal damage that is caused by acetaldehyde accumulation. Other measures evaluated including RelA, superoxide dismutase, catalase, glutathione peroxidase, and glutathione reductase, showed no significant difference between groups. These results suggest that moderate alcohol does not increase CRC risk and may provide beneficial effects that reduce CRC risk, which was evidenced by reduced activity of the inflammatory pathway and lower DNA damage after alcohol exposure. Together with evidence from human studies, these results provide greater support that moderate alcohol provides a protective effect that reduces CRC risk.